Pyrazolopyridines and analogs thereof

ABSTRACT

Pyrazolopyridin-4-amines, pyrazoloquinolin-4-amines, pyrazolonaphthyridin-4-amines, and 6,7,8,9-tetrahydropyrazoloquinolin-4-amines, pharmaceutical compositions containing the compounds, intermediates, methods of making, and methods of use of these compounds as immunomodulators, for inducing or inhibiting cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases, are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International PatentApplication No. PCT/US04/32480, with an international filing date ofOct. 1, 2004, which claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. Nos. 60/508352, filed Oct. 3, 2003,60/554680, filed Mar. 19, 2004, and 60/603303, filed Aug. 20, 2004, allof which are incorporated herein by reference.

BACKGROUND

In the 1950's the 1H-imidazo[4,5-c]quinoline ring system was developed,and 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline wassynthesized for possible use as an antimalarial agent. Subsequently,syntheses of various substituted 1H-imidazo[4,5-c]quinolines werereported. For example,1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline was synthesized as apossible anticonvulsant and cardiovascular agent. Also, several2-oxoimidazo[4,5-c]quinolines have been reported.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substitutedderivatives thereof were later found to be useful as antiviral agents,bronchodilators and immunomodulators. Subsequently, certain substituted1H-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine,tetrahydroquinolin-4-amine, naphthyridin-4-amine, andtetrahydronaphthyridin-4-amine compounds as well as certain analogousthiazolo and oxazolo compounds were synthesized and found to be usefulas immune response modifiers (IRMs), rendering them useful in thetreatment of a variety of disorders.

But despite important progress in the effort to find immunomodulatingcompounds, there is still a scientific and medical need for compoundsthat have an ability to modulate the immune response, by induction orinhibition of cytokine biosynthesis or other mechanisms.

SUMMARY OF THE INVENTION

A new class of compounds useful for modulating cytokine biosynthesis hasnow been found. In one aspect, the present invention provides suchcompounds, which are of the Formulas I and Ia:

and more specifically the following compounds of the Formulas II, III,IV, V, VI, VII, VIII, IX, and LXXX:

wherein R_(A), R_(B), R′, R″, R_(A1), R_(B1), R₁, R₂, R₃, R_(3a), R,R_(A2), R_(B2), R_(A3), R_(B3), n, and m are as defined below; andpharmaceutically acceptable salts thereof.

The compounds of Formulas I, Ia, II, III, IV, V, VI, VII, VIII, IX, andLXXX are useful as immune response modifiers (IRMs) due to their abilityto modulate cytokine biosynthesis (e.g., induce or inhibit thebiosynthesis or production of one or more cytokines) and otherwisemodulate the immune response when administered to animals. Compounds canbe tested per the test procedures described in the Examples Section.Compounds can be tested for induction of cytokine biosynthesis byincubating human peripheral blood mononuclear cells (PBMC) in a culturewith the compound(s) at a concentration range of 30 to 0.014 μM andanalyzing for interferon (α) or tumor necrosis factor (α) in the culturesupernatant. Compounds can be tested for inhibition of cytokinebiosynthesis by incubating mouse macrophage cell line Raw 264.7 in aculture with the compound(s) at a single concentration of, for example,5 μM and analyzing for tumor necrosis factor (α) in the culturesupernatant. The ability to modulate cytokine biosynthesis, for example,induce the biosynthesis of one or more cytokines, makes the compoundsuseful for treating various conditions such as viral diseases andneoplastic diseases, that are responsive to such changes in the immuneresponse.

In another aspect, the present invention provides pharmaceuticalcompositions that contain the immune response modifier compounds, andmethods of modulating (e.g., inducing or inhibiting) cytokinebiosynthesis in an animal, treating a viral disease in an animal, andtreating a neoplastic disease in an animal, by administering aneffective amount of one or more compounds of the Formulas I, Ia, II,III, IV, V, VI, VII, VIII, IX, and/or LXXX and/or pharmaceuticallyacceptable salts thereof to the animal.

In another aspect, the invention provides methods of synthesizingcompounds of the Formulas I, Ia, II, III, IV, V, VI, VII, VIII, IX, andLXXX and intermediates useful in the synthesis of these compounds.

In another aspect, the invention provides prodrugs of compounds of theinvention as well as pharmaceutical compositions containing theprodrugs.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably.

The terms “comprising” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. Guidance is also provided herein through listsof examples, which can be used in various combinations. In eachinstance, the recited list serves only as a representative group andshould not be interpreted as an exclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

In one aspect, the present invention provides compounds of the formula(I):

wherein:

-   -   R_(A) and R_(B) are each independently selected from the group        consisting of:        -   hydrogen,        -   halogen,        -   alkyl,        -   alkenyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   or when taken together, R_(A) and R_(B) form a fused aryl ring        or heteroaryl ring containing one heteroatom selected from the        group consisting of N and S wherein the aryl or heteroaryl ring        is unsubstituted or substituted by one or more R′″ groups;    -   or when taken together, R_(A) and R_(B) form a fused 5 to 7        membered saturated ring, optionally containing one heteroatom        selected from the group consisting of N and S, and unsubstituted        or substituted by one or more R groups;    -   R is selected from the group consisting of:        -   halogen,        -   hydroxy,        -   alkyl,        -   alkenyl,

2haloalkyl,

-   -   -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;

    -   R′ and R″ are independently selected from the group consisting        of hydrogen and non-interfering substitutents;

    -   R′″ is a non-interfering substituent; and

    -   R₉ is selected from the group consisting of hydrogen and alkyl;

    -   with the proviso that at least one of R_(A), R_(B), R′, or R″ is        other than hydrogen; and with the further proviso that when        R_(A) and R_(B) form a benzene ring unsubstituted or substituted        with chloro, and R′ is hydrogen, then R″ is other than phenyl or        phenyl substituted with methyl, methoxy, chloro, or fluoro;        or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides compounds of theformula (II):

wherein:

-   -   -   R_(A1) and R_(B1) are each independently selected from the            group consisting of:        -   hydrogen,        -   halogen,        -   alkyl,        -   alkenyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;

    -   or when taken together, R_(A1) and R_(B1) form a fused aryl ring        or heteroaryl ring containing one heteroatom selected from the        group consisting of N and S wherein the aryl or heteroaryl ring        is unsubstituted or substituted by one or more R groups, or        substituted by one R₃ group, or substituted by one R₃ group and        one R group;

    -   or when taken together, R_(A1) and R_(B1) form a fused 5 to 7        membered saturated ring, optionally containing one heteroatom        selected from the group consisting of N and S, and unsubstituted        or substituted by one or more R groups;

    -   R is selected from the group consisting of:        -   halogen,        -   hydroxy,        -   alkyl,        -   alkenyl,        -   haloalkyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;

    -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄,        -   —X—Y—X—Y—R₄, and        -   —X—R₅;

    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;

    -   R₃ is selected from the group consisting of:        -   -Z—R₄,        -   -Z—X—R₄,        -   -Z—X—Y—R₄,        -   -Z—X—Y—X—Y—R₄, and        -   -Z—X—R₅;

    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;

    -   Y is selected from the group consisting of:        -   —O—,        -   —S(O)₀₋₂—,        -   —S(O)₂—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C(R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R₄)—,        -   —C(═N—O—R₈)—,        -   —CH(—N(—O—R₈)-Q-R₄)—,

    -   Z is a bond or —O—,

    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

    -   R₅ is selected from the group consisting of

    -   R₆ is selected from the group consisting of ═O and ═S;

    -   R₇ is C₂₋₇ alkylene;

    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;

    -   R₉ is selected from the group consisting of hydrogen and alkyl;

    -   R₁₀ is C₃₋₈ alkylene;

    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;

    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;

    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;

    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and

    -   —S(O)₂—;

    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and

    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7;

    -   with the proviso that at least one of R_(A1), R_(B1), R₁, or R₂        is other than hydrogen; and with the further proviso that when        R_(A1) and R_(B1) form a fused benzene ring unsubstituted or        substituted with chloro, and R₁ is hydrogen, then R₂ is other        than phenyl or phenyl substituted with methyl, methoxy, chloro,        or fluoro;        or a pharmaceutically acceptable salt thereof. For certain        embodiments of Formula II, the above group from which Y is        selected further includes —C(═N—O—R₈)—NH—.

In another embodiment, the present invention provides compounds of theformula (III):

wherein:

-   -   R is selected from the group consisting of:        -   halogen,        -   hydroxy,        -   alkyl,        -   alkenyl,        -   haloalkyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,

2—X—Y—R₄,

-   -   -   —X—Y—X—Y—R₄, and        -   —X—R₅;

    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;

    -   R₃ is selected from the group consisting of:        -   -Z—R₄,        -   -Z—X—R₄,        -   -Z—X—Y—R₄,        -   -Z—X—Y—X—Y—R₄, and        -   -Z—X—R₅;

    -   n is 0 to 4;

    -   m is 0 or 1; with the proviso that when m is 1, then n is 0 or        1;

    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;

    -   Y is selected from the group consisting of:        -   —O—,        -   —S(O)₀₋₂—,        -   —S(O)₂—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C(R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R₄)—,        -   —C(═N—O—R₈)—,        -   —CH(—N(—O—R₈)-Q-R₄)—,

    -   Z is a bond or —O—;

    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

    -   R₅ is selected from the group consisting of

    -   R₆ is selected from the group consisting of ═O and ═S;

    -   R₇ is C₂₋₇ alkylene;

    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;

    -   R₉ is selected from the group consisting of hydrogen and alkyl;

    -   R₁₀ is C₃₋₈ alkylene;

    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;

    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;

    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;

    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and

    -   —S(O)₂—;

    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and

    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7; with the proviso that when RI is hydrogen, m is        0, and R is chloro, then R₂ is other than phenyl or phenyl        substituted with methyl, methoxy, chloro, or fluoro;        or a pharmaceutically acceptable salt thereof. For certain        embodiments of Formula III, the above group from which Y is        selected further includes —C(═N—O—R₈)—NH—.

In other embodiments, the present invention provides compounds of theformulas (IV, V, VI, and VII):

wherein:

-   -   R is selected from the group consisting of:        -   halogen,        -   hydroxy,        -   alkyl,        -   alkenyl,        -   haloalkyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄,        -   —X—Y—X—Y—R₄, and        -   —X—R₅;    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;    -   R₃ is selected from the group consisting of:        -   -Z-R₄,        -   -Z-X—R₄,        -   -Z-X—Y—R₄,        -   -Z-X—Y—X—Y—R₄, and        -   -Z-X—R₅;    -   n is 0 or 1;    -   m is 0 or 1;    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of:        -   —O—,        -   —S(O)₀₋₂—,        -   —S(O)₂—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C(R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R₄)—,        -   —C(═N—O—R₈)—,        -   —CH(—N(—O—R₈)-Q-R₄)—,    -   Z is a bond or —O—;    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7;        or a pharmaceutically acceptable salt thereof. For certain        embodiments of Formulas IV, V, VI, and VII, the above group from        which Y is selected further includes —C(═N—O—R₈)—NH—. For        certain of these embodiments, the compound or salt is selected        from the group consisting of the formulas (IV and VII):        or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of theformula (VIII):

wherein:

-   -   R is selected from the group consisting of:        -   halogen,        -   hydroxy,        -   alkyl,        -   alkenyl,        -   haloalkyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄,        -   —X—Y—X—Y—R₄, and        -   —X—R₅;    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;    -   n is 0 to 4;    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of:        -   —O—,        -   —S(O)₀₋₂—,        -   —S(O)₂—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C(R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R₄)—,        -   —C(═N—O—R₈)—,        -   —CH(—N(—O—R₈)-Q-R₄)—,    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7;        or a pharmaceutically acceptable salt thereof. For certain        embodiments of Formula VIII, the above group from which Y is        selected further includes —C(═N—O—R₈)—NH—.

In another embodiment, the present invention provides compounds of theformula (IX):

wherein:

-   -   R_(A2) and R_(B2) are each independently selected from the group        consisting of:        -   hydrogen,        -   halogen,        -   alkyl,        -   alkenyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄,        -   —X—Y—X—Y—R₄, and        -   —X—R₅;    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of:

2—O—,

-   -   -   —S(O)₀₋₂—,        -   —S(O)₂—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C(R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R₄)—,        -   —C(═N—O—R₈)—,        -   —CH(—N(—O—R₈)-Q-R₄)—,

    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

    -   R₅ is selected from the group consisting of

    -   R₆ is selected from the group consisting of ═O and ═S;

    -   R₇ is C₂₋₇ alkylene;

    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;

    -   R₉ is selected from the group consisting of hydrogen and alkyl;

    -   R₁₀ is C₃₋₈ alkylene;

    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;

    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;

    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;

    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and

    -   —S(O)₂—;

    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and

    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7;

    -   with the proviso that at least one of R_(A2), R_(B2), R₁, or R₂        is other than hydrogen;        or a pharmaceutically acceptable salt thereof. For certain        embodiments of Formula IX, the above group from which Y is        selected further includes —C(═N—O—R₈)—NH—.

In another embodiment, the present invention provides compounds of theformula (Ia):

wherein:

-   -   R_(A3) and R_(B3) are each independently selected from the group        consisting of:        -   hydrogen,        -   halogen,        -   alkyl,        -   alkenyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   or when taken together, R_(A3) and R_(B3) form a fused aryl ring        or heteroaryl ring containing one heteroatom or 5 to 7 membered        saturated ring optionally containing one heteroatom wherein the        heteroatom is selected from the group consisting of N and S and        wherein the aryl, heteroaryl, or 5 to 7 membered saturated ring        optionally containing one heteroatom is unsubstituted or        substituted by one or more non-interfering substituents;    -   R′ and R″ are independently selected from the group consisting        of hydrogen and non-interfering substitutents; and    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   with the proviso that at least one of R_(A3), R_(B3), R′, or R″        is other than hydrogen; and with the further proviso that when        R_(A3) and R_(B3) form a benzene ring unsubstituted or        substituted with chloro, and R′ is hydrogen, then R″ is other        than phenyl or phenyl substituted with methyl, methoxy, chloro,        or fluoro;        or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides compounds of thefollowing formula (LXXX):

wherein:

-   -   R is selected from the group consisting of:        -   halogen,        -   alkyl,        -   alkenyl,        -   trifluoromethyl, and        -   dialkylamino;    -   n is 0 or 1;        -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄,        -   —X—Y—X—Y—R₄, and        -   —X—R₅;    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;    -   R₃a is selected from the group consisting of:        -   —Y′—R₄,    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of:        -   —O—,        -   —S(O)₀₋₂—,        -   —S(O)2—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C (R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R4)—,        -   —C(═N—O—R₈)—,        -   —C(═N—O—R₈)—NH—,        -   —CH(—N(—O—R₈)-Q-R₄)—,    -   Y′ is selected from the group consisting Of —S(O)₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, and —C(R₆)—N(R₈)—;    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7;        or a pharmaceutically acceptable salt thereof.

Compounds of Formula LXXX are not only useful for modulating cytokinebiosynthesis, but certain of these compounds are useful, for example, asprodruges and/or intermediates in the preparation of compounds ofFormulas I, Ia, II, III, and VIII.

In another embodiment, the present invention provides compound of theformula (II-1):

wherein:

-   -   Y″ is selected from the group consisting of —C(O)—, —C(O)—O—,        and —C(═NR₉)—;    -   R₁₁ is alkyl that is unsubstituted or substituted by one or more        substituents selected from the group consisting of halogen,        hydroxy, nitro, cyano, carboxy, C₁₋₄ alkoxy, aryl, heteroaryl,        arylC₁₋₄alkylenyl, heteroarylC₁₋₄ alkylenyl, haloC₁₋₄ alkyl,        haloC₁₋₄ alkoxy, —O—C(O)—CH₃, —CO₂CH₃, —CONH₂, —O—CH₂—CONH₂,        —NH₂, and —SO₂—NH₂;    -   R_(A1) and R_(B1) are each independently selected from the group        consisting of:        -   hydrogen,        -   halogen,        -   alkyl,        -   alkenyl,        -   alkoxy,        -   alkylthio and        -   —N(R₉)₂;    -   or when taken together, R_(A1) and R_(B1) form a fused aryl ring        or heteroaryl ring containing one heteroatom selected from the        group consisting of N and S wherein the aryl or heteroaryl ring        is unsubstituted or substituted by one or more R groups, or        substituted by one R₃ group, or substituted by one R₃ group and        one R group;        or when taken together, R_(A1) and R_(B1) form a fused 5 to 7        membered saturated ring, optionally containing one heteroatom        selected from the group consisting of N and S, and unsubstituted        or substituted by one or more R groups;    -   R is selected from the group consisting of:        -   halogen,        -   hydroxy,        -   alkyl,        -   alkenyl,        -   haloalkyl,        -   alkoxy,        -   alkylthio, and        -   —N(R₉)₂;    -   R₁ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄,        -   —X—Y—X—Y—R₄, and        -   —X—R₅;    -   R₂ is selected from the group consisting of:        -   —R₄,        -   —X—R₄,        -   —X—Y—R₄, and        -   —X—R₅;    -   R₃ is selected from the group consisting of:        -   -Z-R₄,        -   -Z-X—R₄,        -   -Z-X—Y—R₄,        -   -Z-X—Y—X—Y—R₄, and        -   -Z-X—R₅;    -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of:        -   —O—,        -   —S(O)₀₋₂—,        -   —S(O)₂—N(R₈)—,        -   —C(R₆)—,        -   —C(R₆)—O—,        -   —O—C(R₆)—,        -   —O—C(O)—O—,        -   —N(R₈)-Q-,        -   —C(R₆)—N(R₈)—,        -   —O—C(R₆)—N(R₈)—,        -   —C(R₆)—N(OR₉)—,        -   —O—N(R₈)-Q-,        -   —O—N═C(R₄)—,        -   —C(═N—O—R₈)—,        -   —C(═N—O—R₈)—NH—,        -   —CH(—N(—O—R₈)-Q-R₄)—,    -   Z is a bond or —O—;    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7;    -   with the proviso that at least one of R_(A1), R_(B1), R₁, or R₂        is other than hydrogen; and with the further proviso that when        R_(A1) and R_(B1) form a fused benzene ring unsubstituted or        substituted with chloro, and R₁ is hydrogen, then R₂ is other        than phenyl or phenyl substituted with methyl, methoxy, chloro,        or fluoro;        or a pharmaceutically acceptable salt thereof For certain        embodiments, Y″ is selected from the group consisting of —C(O)—        and —C(O)—O—, and R₁₁ is C₁₋₆ alkyl.

Compounds and salts of Formula II-1 are useful as prodrugs for compoundsand salts of Formulas I, Ia, II, III, IV, V, VI, VII, VIII, and IX.

Herein, “non-interfering” means that the ability of the compound orsalt, which contains a non-interfering substituent, to modulate (e.g.,induce or inhibit) the biosynthesis of one or more cytokines is notdestroyed by the non-interfering substitutent. Illustrativenon-interfering R′ groups include those described herein for R₁.Illustrative non-interfering R″ groups include those described hereinfor R₂. Illustrative non-interfering substituents (e.g., R′″) for asubstituted, fused aryl or heteroaryl ring, formed when R_(A) and R_(B)(in Formula I) or R_(A3) and R_(B3) (in Formula Ia) are taken together,include those described herein for R and R₃. Illustrativenon-interfering substituents for a substituted, fused 5 to 7 memberedsaturated ring optionally containing one heteroatom, formed when R_(A)and R_(B) (in Formula I) or R_(A3) and R_(B3) (in Formula Ia) are takentogether, include those described herein for R.

As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwisespecified, these groups contain from 1 to 20 carbon atoms, with alkenylgroups containing from 2 to 20 carbon atoms, and alkynyl groupscontaining from 2 to 20 carbon atoms. In some embodiments, these groupshave a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclicor polycyclic and preferably have from 3 to 10 ring carbon atoms.Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl,cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstitutedbornyl, norbornyl, and norbornenyl.

Unless otherwise specified, “alkylene”, “alkenylene”, and “alkynylene”are the divalent forms of the “alkyl”, “alkenyl”, and “alkynyl” groupsdefined above. The terms, “alkylenyl”, “alkenylenyl”, and “alkynylenyl”are use when “alkylene”, “alkenylene”, and “alkynylene”, respectively,are substituted. For example, an arylalkylenyl group comprises analkylene moiety to which an aryl group is attached.

The term “haloalkyl” is inclusive of groups that are substituted by oneor more halogen atoms, including perfluorinated groups. This is alsotrue of other groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl.

Unless otherwise indicated, the term “heteroatom” refers to the atoms O,S, or N.

The term “heteroaryl” includes aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N). In someembodiments, the term “heteroaryl” includes a ring or ring system thatcontains 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O, S, and Nas the heteroatoms. Suitable heteroaryl groups include furyl, thienyl,pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl,pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl,benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl,isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl,1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl,thiadiazolyl, and so on.

The term “heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N) and includes all ofthe fully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. In some embodiments, the term“heterocyclyl” includes a ring or ring system that contains 2-12 carbonatoms, 1-3 rings, 1-4 heteroatoms, and O, S, and N as the heteroatoms.Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl,morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl,piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl,tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl),1,4-oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl,aziridinyl, azetidinyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl,3-azabicyclo[3.2.2]non-3-yl, and the like.

The term “heterocyclyl” includes bicylic and tricyclic heterocyclic ringsystems. Such ring systems include fused and/or bridged rings and spirorings. Fused rings can include, in addition to a saturated or partiallysaturated ring, an aromatic ring, for example, a benzene ring. Spirorings include two rings joined by one spiro atom and three rings joinedby two spiro atoms.

The terms “arylene,” “heteroarylene,” and “heterocyclylene” are thedivalent forms of the “aryl,” “heteroaryl,” and “heterocyclyl” groupsdefined above. The terms, “arylenyl”, “heteroarylenyl”, and“heterocyclylenyl” are used when “arylene,” “heteroarylene,” and“heterocyclylene”, respectively, are substituted. For example, analkylarylenyl group comprises an arylene moiety to which an alkyl groupis attached.

The term “fused aryl ring” includes fused carbocyclic aromatic rings orring systems. Examples of fused aryl rings include benzo, naphtho,fluoreno, and indeno. In certain embodiments, the fused aryl ring isbenzo.

The term “fused heteroaryl ring” includes the fused forms of 5 or 6membered aromatic rings that contain one heteroatom selected from S andN. In certain embodiments, the fused heteroaryl ring is pyrido orthieno. In certain embodiments, the fused heteroaryl ring is pyrido. Incertain of these embodiments, the pyrido ring is

wherein the highlighted bond indicates the position where the ring isfused.

The term “fused 5 to 7 membered saturated ring” includes rings which arefully saturated except for the bond where the ring is fused. In certainembodiments, the ring is a cyclohexene ring. In certain embodimentswherein one heteroatom (N or S) is present, the ring is tetrahydropyridoor dihydrothieno. In certain embodiments, the ring is tetrahydropyrido.In certain of these embodiments, the ring is

wherein the highlighted bond indicates the position where the ring isfused.

When a group (or substituent or variable) is present more than once inany formula described herein, each group (or substituent or variable) isindependently selected, whether explicitly stated or not. For example,for the formula —N(R₈)—C(R₆)—N(R₈)— each R₈ group is independentlyselected. In another example, when an R₂ and an R₃ group both contain anR4 group, each R4 group is independently selected. In a further example,when more than one Y group is present (i.e., R₂ and R₃ both contain a Ygroup) and each Y group contains one or more R₈ groups, then each Ygroup is independently selected, and each R₈ group is independentlyselected.

The invention is inclusive of the compounds described herein and saltsthereof, in any of their pharmaceutically acceptable forms, includingisomers (e.g., diastereomers and enantiomers), solvates, polymorphs,prodrugs, and the like. In particular, if a compound is opticallyactive, the invention specifically includes each of the compound'senantiomers as well as racemic mixtures of the enantiomers. It should beunderstood that the term “compound” or the term “compounds” includes anyor all of such forms, whether explicitly stated or not (although attimes, “salts” are explicitly stated).

The term “prodrug” means a compound that is transformed in vivo to yielda compound of the invention or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvaious mechanisms, such as through hydrolysis, for example, in theblood. A discussion of the use of prodrugs is provided by T. Higuchi andW. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as C₁₋₈ alkyl, C₂₋₁₂ alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyolacton-4-yl, di-N,N—C₁₋₂alkylaminoC₂₋₃ alkyl (such as β-dimethylaminoethyl), carbamoyl-C₁₋₂alkyl, N,N-diC₁₋₂ alkylcarbamoyl-C₁₋₂ alkyl and piperidino-,pyrolidino-, or morpholinoC₂₋₃ alkyl.

If a compound of the present invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as C₁₋₆ alkanoyloxymethyl,1-(C₁₋₆ alkanoyloxy)ethyl, 1-methyl-1-(C₁₋₆ alkanoyloxy)ethyl, C₁₋₆alkoxycarbonyloxymethyl, N—(C₁₋₆ alkoxycarbonyl)aminomethyl, succinoyl,C₁₋₆ alkanoyl, α-aminoC₁₋₄ alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,P(O)(O—C₁₋₆ alkyl)₂ or glycosyl (the radical resulting from the removalof a hydroxyl group of the hemiacetal form of a carbohydrate).

A prodrug can also be formed by replacement of a hydrogen atom in the4-amino group or in another amino group in a compound of the presentinvention with a group such as R″″-carbonyl, R″″—O-carbonyl,N(R″″)(R′″″)-carbonyl where R″″ and R′″″ are each independentlyC₁₋₁₀alkyl, C₃₋₇ cycloalkyl, benzyl, or R″″-carbonyl is a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY′″wherein Y′″ is H, C₁₋₆ alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is C₁₋₄alkyl and Y₁ is C₁₋₆ alkyl, carboxyC₁₋₆ alkyl, aminoC₁₋₄ alkyl ormono-N— or di-N,N—C₁₋₆ alkylaminoalkyl, —C(Y₂)Y₃ wherein Y₂ is H ormethyl and Y₃ is mon-N— or di-N,N—C₁₋₆ alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

Compounds and intermediates of the present invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. The term “tautomer” or “tautomeric form” refersto structural isomers of different energies which are interconvertiblevia a low energy barrier. For exmple proton tautomers (protrotropictautomers) include interconversions via migration of a proton, such asketo-enol and imine-enamine isomerizations. In another example, whencompounds of the present invention have a hydrogen atom at the2-position, proton migration between the 2- and 3-positions may occur.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The present invention embraces bothsolvated and unsolvated forms.

In some embodiments, compounds of the invention (for example, compoundsof Formulas Ia and I-IX, including embodiments thereof described herein)induce the biosynthesis of one or more cytokines, for example, IFN-αand/or TNF-α.

In some embodiments, compounds of the invention (for example, compoundsof Formulas Ia and I-IX, including embodiments thereof described herein)inhibit the biosynthesis of one or more cytokines, for example, TNF-α.

For any of the compounds presented herein, each one of the followingvariables (e.g., R, R′, R″, R′″, R₁, R₂, R₃, n, m, A, X, Y, Z, and soon) in any of its embodiments can be combined with any one or more ofthe other variables in any of their embodiments and associated with anyone of the formulas described herein, as would be understood by one ofskill in the art. Each of the resulting combinations of variables is anembodiment of the present invention.

For certain embodiments of Formula I, each of R, R′, R″, and R′″ isindependently a non-interfering substituent. For certain embodiments,each R′ and R″ is independently selected from the group consisting ofhydrogen and non-interfering substituents.

In some embodiments of Formula I, R_(A) and R_(B) are each independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkenyl,alkoxy, alkylthio, and —N(R₉)₂; or when taken together, R_(A) and R_(B)form a fused aryl ring or heteroaryl ring containing one heteroatomselected from the group consisting of N and S wherein the aryl orheteroaryl ring is unsubstituted or substituted by one or morenon-interfering substituents; or when taken together, R_(A) and R_(B)form a fused 5 to 7 membered saturated ring, optionally containing oneheteroatom selected from the group consisting of N and S, andunsubstituted or substituted by one or more substituents selected fromthe group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl,alkoxy, alkylthio, and —N(R₉)₂.

In some embodiments of Formula I, R_(A) and R_(B) are each independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkenyl,alkoxy, alkylthio, and —N(R₉)₂; or when taken together, R_(A) and R_(B)form a fused aryl ring or heteroaryl ring containing one heteroatomselected from the group consisting of N and S wherein the aryl orheteroaryl ring is unsubstituted or substituted by one or more R′″groups; or when taken together, R_(A) and R_(B) form a fused 5 to 7membered saturated ring, optionally containing one heteroatom selectedfrom the group consisting of N and S, and unsubstituted or substitutedby one or more R groups; wherein each R is independently selected fromthe group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl,alkoxy, alkylthio, and —N(R₉)₂.

In some embodiments of Formula I, R_(A) and R_(B) are each independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkenyl,alkoxy, alkylthio, and —N(R₉)₂.

In some embodiments of Formula I, R_(A) and R_(B) form a fused aryl orheteroaryl ring.

In some embodiments of Formula I, R_(A) and R_(B) form a fused arylring.

In some embodiments of Formula I, R_(A) and R_(B) form a fusedheteroaryl ring.

In some embodiments of Formula I, R_(A) and R_(B) form a fused 5 to 7membered saturated ring.

In some embodiments of Formula I, R_(A) and R_(B) form a fused 5 to 7membered saturated ring containing one heteroatom selected from thegroup consisting of N and S. In certain embodiments the heteroatm is N.

In some embodiments of Formula II, R_(A1) and R_(B1) are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio and —N(R₉)₂; or when taken together,R_(A1) and R_(B1) form a fused aryl ring or heteroaryl ring containingone heteroatom selected from the group consisting of N and S wherein thearyl or heteroaryl ring is unsubstituted or substituted by one or more Rgroups, or substituted by one R₃ group, or substituted by one R₃ groupand one R group; or when taken together, R_(A1) and R_(B1) form a fused5 to 7 membered saturated ring, optionally containing one heteroatomselected from the group consisting of N and S, and unsubstituted orsubstituted by one or more R groups; wherein R is selected from thegroup consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy,alkylthio, and —N(R₉)₂; and R₃ is selected from the group consisting of-Z-R₄, -Z-X—R₄, -Z-X—Y—R₄, -Z-X—Y—X—Y—R₄, and -Z-X—R₅.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fused arylring.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fusedbenzene ring which is unsubstituted.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fusedheteroaryl ring.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fusedpyridine ring which is unsubstituted.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fused 5 to 7membered saturated ring, optionally containing one heteroatom selectedfrom the group consisting of N and S, wherein the ring is unsubstituted.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fused 5 to 7membered saturated ring.

In some embodiments of Formula II, R_(A1) and R_(B1) form a fused 5 to 7membered saturated ring containing one heteroatom selected from thegroup consisting of N and S. In certain embodiments the heteroatom is N.

In some embodiments of Formula IX, R_(A2) and R_(B2) are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂. In certain of theseembodiments, R_(A2) and RB₂ are each independently alkyl. In certain ofthese embodiments, R_(A2) and RB₂ are each methyl.

In some embodiments of Formula Ia, R_(A3) and R_(B3) are eachindependently selected from the group consisting of hydrogen, halogen,alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂; or when taken together,R_(A3) and R_(B3) form a fused aryl ring or heteroaryl ring containingone heteroatom or a 5 to 7 membered saturated ring containing oneheteroatom wherein the heteroatom is selected from the group consistingof N and S and wherein the aryl, heteroaryl, or 5 to 7 memberedsaturated ring is unsubstituted or substituted by one or morenon-interfering substituents.

In some embodiments (e.g., of Formulas I through VIII), R is selectedfrom the group consisting of halogen, hydroxy, alkyl, alkenyl,haloalkyl, alkoxy, alkylthio, and —N(R₉)₂.

In some embodiments (e.g., of Formulas I through VIII and particularlyFormula III), R is selected from the group consisting of hydroxy andmethoxy. In certain of these embodiments (e.g., of Formula III), m is 0.In certain of these embodiments, m is 0 and n is 1.

In some embodiments (e.g., of Formula LXXX), R is selected from thegroup consisting of halogen, alkyl, alkenyl, trifluoromethyl, anddialkylamino.

In some embodiments of Formulas I and Ia, R′ is selected from the groupconsisting of —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄, and —X—R₅; wherein:

-   -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of —O—, —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,        —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—.    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7. In certain of these embodiments, the above group        from which Y is selected also includes —C(═N—O—R₈)—NH—. In        certain of these embodiments of Formulas I and Ia, Y is selected        from the group consisting of —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—,        —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,        —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,        and R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl. In certain        of these embodiments, Y is selected from the group consisting of        —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—,        —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—,        —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, and arylalkylenyl; and Q is selected from the        group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—,        —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and    -   —C(R₆)—N(OR₉)—.

In some embodiments of Formulas I and Ia, R′ is selected from the groupconsisting of —R₄, —X—R₄, —X—Y—R₄, —X—Y—X′—Y′—R₄, and —X—R₅; wherein:

-   -   X is alkylene that is optionally interrupted or terminated by        heterocyclylene and optionally interrupted by one —O— group;    -   Y is selected from the group consisting of —O—, —S(O)₂—,        —S(O)₂—N(R₈)—, —C(O)—, —C(O)—O—, —O—C(O)—, —N(R₈)-Q-,        —C(O)—N(R₈)—,    -   X¹ is selected from the group consisting of alkylene and        arylene;    -   Y¹ is selected from the group consisting of —S—, —C(O)—,        —C(O)—O—, —C(O)—N(R₈)—, —S(O)₂—N(R₈)—, and —N(R₈)—C(O)—;    -   R₄ is selected from the group consisting of hydrogen, alkyl,        aryl, heterocyclyl, heteroaryl, heteroarylalkylenyl, alkynyl,        arylalkylenyl, and arylalkenylenyl, wherein the alkyl, aryl,        arylalkylenyl, heterocyclyl, heteroaryl, and heteroarylalkylenyl        groups can be unsubstituted or substituted by one or more        substituents independently selected from the group consisting of        alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, cyano,        aryl, aryloxy, heteroaryl, heterocyclyl, amino, dialkylamino,        and in the case of alkyl and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of:    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—, and        —N(R₄)—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(O)—O—, and —C(O)—S—;    -   W is selected from the group consisting of a bond and —C(O)—;        and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7.

In certain of these embodiments of Formulas I and Ia, X is alkylene thatis optionally interrupted or terminated by heterocyclylene; Y isselected from the group consisting of —S(O)₂—, —C(O)—, —C(O)—O—,—O—C(O)—, —N(R₈)-Q-, —C(O)—N(R₈)—,

R₄ is selected from the group consisting of hydrogen, alkyl, aryl,heterocyclyl, heteroaryl, heteroarylalkylenyl, alkynyl, andarylalkenylenyl, wherein the alkyl, aryl, heterocyclyl, heteroaryl, andheteroarylalkylenyl groups can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, aryl,aryloxy, heteroaryl, heterocyclyl, amino, dialkylamino, and in the caseof alkyl and heterocyclyl, oxo; and R₈ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, andarylalkylenyl.

In some embodiments of Formulas I and Ia, R′ is selected from the groupconsisting of alkyl, arylalkylenyl, heterocyclylalkylenyl whereinheterocyclyl is unsubstituted or substituted with one or two oxo groups,aryloxyalkylenyl, hydroxyalkylenyl, aminoalkylenyl, haloalkylenyl,alkylsulfonylalkylenyl, —X—Y—R₄, and —X—R₅; wherein X is alkylene; Y is—N(R₈)—C(O)—, —N(R₈)—S(O)₂—, —N(R₈)—C(O)—N(R₈)—, —N(R₈)—C(S)—N(R₈)—,—N(R₈)—S(O)₂—N(R₈)—, or

R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In some embodiments of Formulas I and Ia, R′ is selected from the groupconsisting of C₁₋₅ alkyl, C₂₋₅ alkynyl, arylC₁₋₄ alkylenyl,cycloalkylC₁₋₄ alkylenyl, C₁₋₄ alkyl-S(O)₂—C₁₋₄ alkylenyl,aryl-S(O)₂—C₁₋₄ alkylenyl, C₁₋₄ alkyl-S(O)₂—C₁₋₄ alkylenyl-O—C₁₋₄alkylenyl, C₁₋₄ alkyl-S(O)₂—NH—C₁₋₄ alkylenyl, hydroxyC₁₋₄ alkylenyl,haloC₁₋₄ alkylenyl, aminoC₁₋₄ alkylenyl, C₁₋₄ alkyl-C(O)—O—C₁₋₄alkylenyl, C₁₋₆ alkyl-C(O)—NH—C₁₋₄ alkylenyl, aryl-C(O)—NH—C₁₋₄alkylenyl wherein aryl is unsubstituted or substituted with one or twohalogen groups, heteroaryl-C(O)-NH—C₁₋₄ alkylenyl, di(C₁₋₄alkyl)amino-S(O)₂—NH—C₁₋₄ alkylenyl, aryl-S(O)₂—NH—C₁₋₄ alkylenyl,aryl-NH—C(O)—NH—C₁₋₄ alkylenyl, heteroaryl-NH—C(S)—NH—C₁₋₄ alkylenyl,di(C₁₋₄ alkyl)amino-C(O)—NH—C₁₋₄ alkylenyl, C₁₋₄ alkylamino-C(O)—NH—C₁₋₄alkylenyl, di(C₁₋₄ alkyl)amino-S(O)₂—C₁₋₄ alkylenyl, C₁₋₄alkylamino-S(O)₂—C₁₋₄ alkylenyl, amino-S(O)₂—C₁₋₄ alkylenyl,heteroarylC₁₋₄ alkylenyl wherein heteroaryl is unsubstituted orsubstituted by a substituent selected from the group consisting of aryl,heteroaryl, and alkyl, and heterocyclylC₁₋₄ alkylenyl whereinheterocyclyl is unsubstituted or substituted by one or two substituentsselected from the group consisting of heteroaryl and oxo. In someembodiments of Formulas I and Ia, the above group from which R′ isselected also includes hydrogen, C₁₋₄ alkyl-S(O)₂—C₁₋₄ alkylenyl-NH—C₁₋₄alkylenyl, cyanoC₁₋₄ alkylenyl, hydroxyiminoC₂₋₅ alkylenyl, C₁₋₄alkoxyiminoC₂₋₅ alkylenyl, amino(hydroxyimino)C₂₋₅ alkylenyl,NH₂—C(O)—C₁₋₄ alkylenyl, C₁₋₄ alkyl-C(O)—C₁₋₄ alkylenyl, C₁₋₆alkyl-O—C(O)—NH—C₁₋₄ alkylenyl, heterocyclyl-C(O)—NH-C₁₋₄ alkylenyl; andwherein heteroaryl is unsubstituted or substituted by a substituentselected from the group consisting of aryl, arylalkylenyl, heteroaryl,and alkyl; and wherein heterocyclyl is unsubstituted or substituted byone or two substituents selected from the group consisting ofarylalkylenyl, heteroaryl, and oxo.

In some embodiments of Formulas I and Ia, R′ is selected from the groupconsisting of methyl, ethyl, propyl, 2-methylpropyl, 2,2-dimethylpropyl,butyl, pent-4-ynyl, 2-phenylethyl, 2-hydroxy-2-methylpropyl,4-hydroxybutyl, 2-amino-2-methylpropyl, 2-aminoethyl, 4-aminobutyl,2-methanesulfonylethyl, 2-(propylsulfonyl)ethyl,4-(methylsulfonyl)butyl, 3-(phenylsulfonyl)propyl,2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl, 4-acetoxybutyl,4-methanesulfonylaminobutyl, 2-methyl-2-[(methylsulfonyl)aminopropyl,2-(2-propanesulfonylamino)ethyl, 2-(benzenesulfonylamino)ethyl,2-(dimethylaminosulfonylamino)ethyl, 4-(aminosulfonyl)butyl,4-[(methylamino)sulfonyl]butyl, 4-[(dimethylamino)sulfonyl]butyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-[(cyclopropylcarbonyl)amino]-2-methylpropyl,2-(isobutyrylamino)-2-methylpropyl, 2-methyl-2-(propionylamino)propyl,2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl,2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl,2-(acetylamino)-2-methylpropyl, 2-(benzoylamino)ethyl,2-(benzoylamino)-2-methylpropyl,2-[(4-fluorobenzoyl)amino]-2-methylpropyl,2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl,2-[(pyridin-3-ylcarbonyl)amino]ethyl, 2-(isobutyrylamino)ethyl,2-{[(isopropylamino)carbonyl]amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl,4-(4-pyridin-2-ylpiperazin-1-yl)butyl, 3-(3-methylisoxazol-5-yl)propyl,3-(3-isopropylisoxazol-5-yl)propyl, 3-(3-phenylisoxazol-5-yl)propyl,3-(3-pyridin-3-ylisoxazol-5-yl)propyl,4-(3,5,5-trimethyl-1,2,4-oxadiazol4(5H)-yl)butyl,4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl,2-{[(pyridin-3-ylamino)carbonothioyl]amino}ethyl,2-{[(dimethylamino)carbonyl]amino}ethyl, and2-{[(phenylamino)carbonyl]amino}ethyl. In some embodiments of Formulas Iand Ia, the above group from which R′ is selected also includeshydrogen, hydroxymethyl, 2-cyano-2-methylpropyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl,2-methyl-2-(methylsulfonyl)propyl,2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl,2-[(methylsulfonyl)amino]ethyl, 3-[(methylsulfonyl)amino]propyl,2-[(cyclopropylcarbonyl)amino]ethyl, 2-(acetylamino)ethyl,2-(propionylamino)ethyl, 2-[(4-fluorobenzoyl)amino]ethyl,2-{[(ethylamino)carbonyl]amino}ethyl,2-[(morpholin-4-ylcarbonyl)amino]ethyl, 2-[(ethoxycarbonyl)amino]ethyl,2-(1,1-dioxidoisothiazolidin-2-yl)ethyl, 3-(1H-pyrrol-3-yl)propyl,3-(1-benzyl-1H-pyrrol-3-yl)propyl,3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl,3-(5-butylisoxazol-3-yl)propyl, 3-(5-phenylisoxazol-3-yl)propyl,3-(5-pyridin-3-ylisoxazol-3-yl)propyl,2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl,2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl, 4-(hydroxyimino)butyl,4-(methoxyimino)butyl, and 5-amino-5-(hydroxyimino)pentyl.

In some embodiments of Formulas I and Ia, R′ is is selected from thegroup consisting of methyl, ethyl, propyl, butyl, 2-methylpropyl,2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl,2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, and4-methanesulfonylaminobutyl. In some embodiments of Formulas I and Ia,the above group from which R′ is selected also includes3-amino-2,2-dimethyl-3-oxopropyl and 2,2-dimethyl-4-oxopentyl.

In some embodiments of Formulas I and Ia, R″ is selected from the groupconsisting of —R₄, —X—R₄, —X—Y—R₄, and —X—R₅; wherein:

-   -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of —O—, —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,        —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7. In certain of these embodiments, the above group        from which Y is selected also includes —C(═N—O—R₈)—NH—. In        certain of these embodiments of Formulas I and Ia, Y is selected        from the group consisting of —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—,        —C(R₆)—O—, —)—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,        —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   and R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl. In certain        of these embodiments of Formulas I and Ia, Y is selected from        the group consisting of —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—,        —C(R₆)—O—, —O—C(R₆, —O—C(O)—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,        —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of R₈ is selected from        the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and        arylalkylenyl; and Q is selected from the group consisting of a        bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—,        —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—.

In some embodiments of Formulas I and Ia, R″ is selected from the groupconsisting of —R₄, —X—R₄, and —X—Y—R₄; wherein:

-   -   X is alkylene that is optionally terminated by arylene or        heterocyclylene;    -   Y is selected from the group consisting of —S(O)₂—, —C(O)—,        —C(O)—O—, —N(R₈)-Q-, —C(O)—N(R₈)—, and    -   R₄ is selected from the group consisting of hydrogen, alkyl,        aryl, arylalkylenyl, aryloxyalkylenyl, heterocyclyl, and        heteroaryl, wherein the alkyl, aryl, aryloxyalkylenyl, and        heterocyclyl groups can be unsubstituted or substituted by one        or more substituents independently selected from the group        consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl,        haloalkoxy, halogen, nitro, hydroxy, cyano, aryl, aryloxy,        heteroaryl, heterocyclyl, and in the case of heterocyclyl, oxo;    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is in selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl; and    -   Q is selected from the group consisting of a bond, —C(O)—,        —S(O)₂—, —C(R₆)—N(R₈)—, and —S(O)₂—N(R₈)—.

In some embodiments of Formulas I and Ia, R″ is selected from the groupconsisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, andhydroxyalkylenyl. In certain embodiments, R″ is selected from the groupconsisting of hydrogen, alkyl, arylalkylenyl, and alkoxyalkylenyl. Incertain embodiments, R″ is selected from the group consisting ofhydrogen, alkyl, and alkoxyalkylenyl.

In some embodiments of Formulas I and Ia, R″ is selected from the groupconsisting of hydrogen, C₁₋₅ alkyl, C₁₋₄ alkoxyC₁₋₄ alkylenyl,hydroxyC₁₋₄ alkylenyl, and arylC₁₋₄ alkylenyl wherein aryl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of chloro, fluoro, methoxy, methyl, cyano, andmethoxycarbonyl. In certain embodiments, R″ is selected from the groupconsisting of hydrogen, C₁₋₅ alkyl, C₁₋₄ alkoxyC₁₋₄ alkylenyl, andarylC₁₋₄ alkylenyl wherein aryl is unsubstituted or substituted by oneor more substituents selected from the group consisting of chloro,fluoro, methoxy, methyl, cyano, and methoxycarbonyl. In certainembodiments, R″ is selected from the group consisting of hydrogen, C₁₋₄alkyl, and C₁₋₄ alkoxyC₁₋₄ alkylenyl.

In some embodiments of Formulas I and Ia, R″ is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl. In certain embodiments, R″ is selected fromthe group consisting of hydrogen, methyl, ethyl, propyl, butyl,2-methoxyethyl, and benzyl. In certain embodiments, R″ is selected fromthe group consisting of hydrogen, methyl, ethyl, propyl, butyl, andbenzyl. In certain embodiments, R″ is selected from the group consistingof methyl, ethyl, propyl, and butyl. In certain embodiments, R″ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methoxyethyl, and 2-hydroxyethyl.

In some embodiments of Formula I, one or more R′″ groups are present. Incertain of these embodiments, R′″ is one or more R groups, or one Rgroup and one R₃ group, or one R₃ group.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄,and —X—R₅; wherein:

-   -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of —O—, —S(O)₀₋₂,        —S(O)₂—N(R₈)—, C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,        —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—, CH(—N(—O—R₈)-Q-R₄)—,    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7. In certain of these embodiments, the above group        from which Y is selected also includes —C(═N—O—R₈)—NH—. In        certain of these embodiments (e.g., of Formulas II through IX        and LXXX), Y is selected from the group consisting of —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)——N(R₈)-Q-,        —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₈)—,    -   R₅ is selected from the group consisting of    -   and R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl. In certain        of these embodiments, Y is selected from the group consisting of        —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—,        —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—,        —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, and arylalkylenyl; and Q is selected from the        group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—,        —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—.        15 In some embodiments (e.g., of Formulas II through IX and        LXXX), R₁ is selected from the group consisting of —R₄, —X—R₄,        —X—Y—R₄, —X—Y—X¹—Y¹—R₄, and —X—R₅; wherein:    -   X is alkylene that is optionally interrupted or terminated by        heterocyclylene and optionally interrupted by one —O— group;    -   Y is selected from the group consisting of —O—, —S(O)₂—,        —S(O)₂—N(R₈)—, —C(O)—, —C(O)—O—, —O—C(O)—, —N(R₈)-Q-,        —C(O)—N(R₈)—,    -   X¹ is selected from the group consisting of alkylene and        arylene;    -   Y¹ is selected from the group consisting of —S—, —C(O)—,        —C(O)—O—, —C(O)—N(R₈)—, —S(O)₂—N(R₈)—, and —N(R₈)—C(O)—;    -   R₄ is selected from the group consisting of hydrogen, alkyl,        aryl, heterocyclyl, heteroaryl, heteroarylalkylenyl, alkynyl,        arylalkylenyl, and arylalkenylenyl, wherein the alkyl, aryl,        arylalkylenyl, heterocyclyl, heteroaryl, and heteroarylalkylenyl        groups can be unsubstituted or substituted by one or more        substituents independently selected from the group consisting of        alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, cyano,        aryl, aryloxy, heteroaryl, heterocyclyl, amino, dialkylamino,        and in the case of alkyl and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—, and        —N(R₄)—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(O)—O—, and —C(O)—S—;    -   W is selected from the group consisting of a bond and —C(O)—;        and    -   a and b are independently integers from 1 to 6 with the proviso        that a +b is ≦7. In certain of these embodiments, X is alkylene        that is optionally interrupted or terminated by heterocyclylene;        Y is selected from the group consisting of —S(O)₂—, —C(O)—,        —C(O)—O—, —O—C(O)—, —N(R₈)-Q-, —C(O)—N(R₈)—,    -   is selected from the group consisting of hydrogen, alkyl, aryl,        heterocyclyl, heteroaryl, heteroarylalkylenyl, alkynyl, and        arylalkenylenyl, wherein the alkyl, aryl, heterocyclyl,        heteroaryl, and heteroarylalkylenyl groups can be unsubstituted        or substituted by one or more substituents independently        selected from the group consisting of alkyl, alkoxy, haloalkyl,        haloalkoxy, halogen, hydroxy, cyano, aryl, aryloxy, heteroaryl,        heterocyclyl, amino, dialkylamino, and in the case of alkyl and        heterocyclyl, oxo; and R₈ is selected from the group consisting        of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and        arylalkylenyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of alkyl, arylalkylenyl,heterocyclylalkylenyl wherein heterocyclyl is unsubstituted orsubstituted with one or two oxo groups, aryloxyalkylenyl,hydroxyalkylenyl, aminoalkylenyl, haloalkylenyl, alkylsulfonylalkylenyl,—X—Y—R₄, and —X—R₅; wherein X is alkylene; Y is —N(R₈)—C(O)—,—N(R₈)—S(O)₂—, —N(R₈)—C(O)—N(R₈)—, —N(R₈)—C(S)—N(R₈)—,—N(R₈)—S(O)₂—N(R₈)—, or

-   -   R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of alkyl, arylalkylenyl,aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, —X—Y—R₄, and—X—R₅; wherein X is alkylene; Y is —N(R₈)—C(O)—, —N(R₈)—S(O)₂—,—N(R₈)—C(O)—N(R₈)—, or

-   -   R₄ is alkyl, aryl, or heteroaryl; and R₅ is

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is—R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is—X—R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is—X—Y-R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is—X—Y—X¹—Y¹—R₅.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is—X—Y—X¹—Y¹—R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is—X—R₅.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of C₁₋₅ alkyl, C₂₋₅ alkynyl, arylC₁₋₄alkylenyl, cycloalkylC₁₋₄ alkylenyl, C₁₋₄ alkyl-S(O)₂-C₁₋₄ alkylenyl,aryl-S(O)₂—C₁₋₄ alkylenyl, C₁₋₄ alkyl-S(O)₂—C₁₋₄ alkylenyl-O—C₁₋₄alkylenyl, C₁₋₄ alkyl-S(O)₂—NH—C₁₋₄ alkylenyl, hydroxyC₁₋₄ alkylenyl,haloC₁₋₄ alkylenyl, aminoC₁₋₄ alkylenyl, C₁₋₄ alkyl-C(O)—O—C₁₋₄alkylenyl, C₁₋₆ alkyl-C(O)—NH—C₁₋₄ alkylenyl, aryl-C(O)—NH—C₁₋₄alkylenyl wherein aryl is unsubstituted or substituted with one or twohalogen groups, heteroaryl-C(O)—NH—C₁₋₄ alkylenyl, di(C₁₋₄alkyl)amino-S(O)₂—NH—C₁₋₄ alkylenyl, aryl-S(O)₂—NH—C₁₋₄ alkylenyl,aryl-NH—C(O)—NH—C₁₋₄ alkylenyl, heteroaryl-NH—C(S)—NH—C₁₋₄ alkylenyl,di(C₁₋₄ alkyl)amino-C(O)—NH—C₁₋₄ alkylenyl, C₁₋₄ alkylamino-C(O)—NH—C₁₋₄alkylenyl, di(C₁₋₄ alkyl)amino-S(O)₂—C₁₋₄ alkylenyl, C₁₋₄alkylamino-S(O)₂—C₁₋₄ alkylenyl, amino-S(O)₂-C₁₋₄ alkylenyl,heteroarylC₁₋₄ alkylenyl wherein heteroaryl is unsubstituted orsubstituted by a substituent selected from the group consisting of aryl,heteroaryl, and alkyl, and heterocyclylC₁₋₄ alkylenyl whereinheterocyclyl is unsubstituted or substituted by one or two substituentsselected from the group consisting of heteroaryl and oxo. In someembodiments (e.g., of Formulas II through IX and LXXX), the above groupfrom which R₁ is selected also includes hydrogen, C₁₋₄ alkyl-S(O)₂—C₁₋₄alkylenyl-NH—C₁₋₄ alkylenyl, cyanoC₁₋₄ alkylenyl, hydroxyiminoC₂₋₅alkylenyl, C₁₋₄ alkoxyiminoC₂₋₅ alkylenyl, amino(hydroxyimino)C₂₋₅alkylenyl, NH₂—C(O)—C₁₋₄ alkylenyl, C₁₋₄ alkyl-C(O)—C₁₋₄ alkylenyl, C₁₋₆alkyl-O—C(O)—NH—C₁₋₄ alkylenyl, heterocyclyl-C(O)—NH—C₁₋₄ alkylenyl; andwherein heteroaryl is unsubstituted or substituted by a substituentselected from the group consisting of aryl, arylalkylenyl, heteroaryl,and alkyl; and wherein heterocyclyl is unsubstituted or substituted byone or two substituents selected from the group consisting ofarylalkylenyl, heteroaryl, alkylcarbonyl, alkylsulfonyl,alkylaminocarbonyl, and oxo.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of C₁₋₅ alkyl, arylC₁₋₄ alkylenyl,cycloalkylC₁₋₄ alkylenyl, C₁₋₄ alkyl-S(O)₂—C₁₋₄ alkylenyl, C₁₋₄alkyl-S(O)₂—NH—C₁₋₄ alkylenyl, hydroxyC₁₋₄ alkylenyl, haloC₁₋₄alkylenyl, aminoC₁₋₄ alkylenyl, C₁₋₆ alkyl-C(O)—NH—C₁₋₄ alkylenyl,aryl-C(O)—NH—C₁₋₄ alkylenyl, heteroaryl-C(O)—NH—C₁₋₄ alkylenyl, di(C₁₋₄alkyl)amino-S(O)₂—NH—C₁₋₄ alkylenyl, aryl-S(O)₂—NH—C₁₋₄ alkylenyl,aryl-NH—C(O)—NH—C₁₋₄ alkylenyl, heteroaryl-NH—C(S)—NH—C₁₋₄ alkylenyl,di(C₁₋₄ alkyl)amino-C(O)—NH—C₁₋₄ alkylenyl, C₁₋₄ alkylamino-C(O)—NH—C₁₋₄alkylenyl, heteroarylC₁₋₄ alkylenyl wherein heteroaryl is unsubstitutedor substituted by a substituent selected from the group consisting ofaryl, heteroaryl, and alkyl, and heterocyclylC₁₋₄ alkylenyl whereinheterocyclyl is unsubstituted or substituted by one or two substituentsselected from the group consisting of heteroaryl and oxo.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkyl-S(O)₂—C₁₋₄alkylenyl, C₁₋₄ alkyl-S(O)₂—NH—C₁₋₄ alkylenyl, hydroxyC₁₋₄ alkylenyl,aminoC₁₋₄ alkylenyl, C₁₋₆ alkyl-C(O)—NH—C₁₋₄ alkylenyl,aryl-C(O)—NH—C₁₋₄ alkylenyl, heteroaryl-C(O)—NH—C₁₋₄ alkylenyl, di(C₁₋₄alkyl)amino-S(O)₂—NH—C₁₋₄ alkylenyl, aryl-S(O)₂—NH—C₁₋₄ alkylenyl,aryl-NH—C(O)—NH—C₁₋₄ alkylenyl, heteroaryl-NH—C(S)—NH—C₁₋₄ alkylenyl,and di(C₁₋₄ alkyl)amino-C(O)—NH—C₁₋₄ alkylenyl, and heterocyclylC₁₋₄alkylenyl wherein heterocyclyl is unsubstituted or substituted with oneor two oxo groups.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, propyl,2-methylpropyl, 2,2-dimethylpropyl, butyl, pent-4-ynyl, 2-phenylethyl,2-hydroxy-2-methylpropyl, 4-hydroxybutyl, 2-amino-2-methylpropyl,2-aminoethyl, 4-aminobutyl, 2-methanesulfonylethyl,2-(propylsulfonyl)ethyl, 4-(methylsulfonyl)butyl,3-(phenylsulfonyl)propyl, 2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl,4-acetoxybutyl, 4-methanesulfonylaminobutyl,2-methyl-2-[(methylsulfonyl)aminopropyl,2-(2-propanesulfonylamino)ethyl, 2-(benzenesulfonylamino)ethyl,2-(dimethylaminosulfonylamino)ethyl, 4-(aminosulfonyl)butyl,4-[(methylamino)sulfonyl]butyl, 4-[(dimethylamino)sulfonyl]butyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-[(cyclopropylcarbonyl)amino]-2-methylpropyl,2-(isobutyrylamino)-2-methylpropyl, 2-methyl-2-(propionylamino)propyl,2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl,2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl,2-(acetylamino)-2-methylpropyl, 2-(benzoylamino)ethyl,2-(benzoylamino)-2-methylpropyl,2-[(4-fluorobenzoyl)amino]-2-methylpropyl,2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl,2-[(pyridin-3-ylcarbonyl)amino]ethyl, 2-(isobutyrylamino)ethyl,2-{[(isopropylamino)carbonyl]amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl,4-(4-pyridin-2-ylpiperazin-1-yl)butyl, 3-(3-methylisoxazol-5-yl)propyl,3-(3-isopropylisoxazol-5-yl)propyl, 3-(3-phenylisoxazol-5-yl)propyl,3-(3-pyridin-3-ylisoxazol-5-yl)propyl,4-(3,5,5-trimethyl-1,2,4-oxadiazol4(5H)-yl)butyl,4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl,2-{[(pyridin-3-ylamino)carbonothioyl]amino}ethyl,2-{[(dimethylamino)carbonyl]amino}ethyl, and2-{[(phenylamino)carbonyl]amino}ethyl. In some embodiments (e.g., ofFormulas II through IX and LXXX), the above group from which R₁ isselected also includes hydrogen, hydroxymethyl, aminomethyl,2-cyano-2-methylpropyl, 3-amino-2,2-dimethyl-3-oxopropyl,2,2-dimethyl-4-oxopentyl, 2-methyl-2-(methylsulfonyl)propyl,2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl,2-[(methylsulfonyl)amino]ethyl, 3-[(methylsulfonyl)amino]propyl,2-[(cyclopropylcarbonyl)amino]ethyl, 2-(acetylamino)ethyl,2-(propionylamino)ethyl, 2-[(4-fluorobenzoyl)amino]ethyl,2-{[(ethylamino)carbonyl]amino}ethyl, piperidin-4-ylmethyl,(1-benzylpiperidin-4-yl)methyl, (1-acetylpiperidin-4-yl)methyl,1-[(propylamino)carbonyl]piperidin-4-yl}methyl,[1-(methylsulfonyl)piperidin-4-yl]methyl,2-[(morpholin-4-ylcarbonyl)amino]ethyl, 2-[(ethoxycarbonyl)amino]ethyl,2-(1,1-dioxidoisothiazolidin-2-yl)ethyl, 3-(1H-pyrrol-3-yl)propyl,3-(1-benzyl-1H-pyrrol-3-yl)propyl,3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl,3-(5-butylisoxazol-3-yl)propyl, 3-(5-phenylisoxazol-3-yl)propyl,3-(5-pyridin-3-ylisoxazol-3-yl)propyl,2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl,2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl, 4-(hydroxyimino)butyl,4-(methoxyimino)butyl, and 5-amino-5-(hydroxyimino)pentyl.

In some embodiments (e.g., of Formula VIII), R₁ is selected from thegroup consisting of methyl, ethyl, propyl, 2-methylpropyl,2,2-dimethylpropyl, butyl, pent-4-ynyl, 2-cyclohexylethyl,2-hydroxy-2-methylpropyl, 4-hydroxybutyl, 2-amino-2-methylpropyl,2-aminoethyl, 4-aminobutyl, 2-methanesulfonylethyl,2-(propylsulfonyl)ethyl, 4-(methylsulfonyl)butyl,3-(phenylsulfonyl)propyl, 2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl,4-acetoxybutyl, 4-methanesulfonylaminobutyl,2-methyl-2-[(methylsulfonyl)aminopropyl,2-(2-propanesulfonylamino)ethyl, 2-benzenesulfonylamino)ethyl,2-(dimethylaminosulfonylamino)ethyl, 4-(aminosulfonyl)butyl,4-[(methylamino)sulfonyl]butyl, 4-[(dimethylamino)sulfonyl]butyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-[(cyclopropylcarbonyl)amino]-2-methylpropyl,2-(isobutyrylamino)-2-methylpropyl, 2-methyl-2-(propionylamino)propyl,2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl,2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl,2-(acetylamino)-2-methylpropyl, 2-(benzoylamino)ethyl,2-(benzoylamino)-2-methylpropyl,2-[(4-fluorobenzoyl)amino]-2-methylpropyl,2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl,2-[(pyridin-3-ylcarbonyl)amino]ethyl, 2-(isobutyrylamino)ethyl,2-{[(isopropylamino)carbonyl]amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl,4-(4-pyridin-2-ylpiperazin-1-yl)butyl, 3-(3-methylisoxazol-5-yl)propyl,3-(3-isopropylisoxazol-5-yl)propyl, 3-(3-phenylisoxazol-5-yl)propyl,3-(3-pyridin-3-ylisoxazol-5-yl)propyl,4-(3,5,5-trimethyl-1,2,4-oxadiazol4(5H)-yl)butyl,4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl,2-{[(pyridin-3-ylamino)carbonothioyl]amino}ethyl,2-{[(dimethylamino)carbonyl]amino}ethyl, and2-{[(phenylamino)carbonyl]amino}ethyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, 2-methylpropyl,2,2-dimethylpropyl, 2-phenylethyl, 2-hydroxy-2-methylpropyl,4-hydroxybutyl, 2-amino-2-methylpropyl, 2-aminoethyl,2-methanesulfonylethyl, 2-(propylsulfonyl)ethyl,4-methanesulfonylaminobutyl, 2-methyl-2-[(methylsulfonyl)aminopropyl,2-(2-propanesulfonylamino)ethyl, 2-(benzenesulfonylamino)ethyl,2-(dimethylaminosulfonylamino)ethyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-(isobutyrylamino)-2-methylpropyl,2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl,2-(acetylamino)-2-methylpropyl, 2-(benzoylamino)ethyl,2-(benzoylamino)-2-methylpropyl, 2-[(pyridin-3-ylcarbonyl)amino]ethyl,2-(isobutyrylamino)ethyl,2-{[(isopropylamino)carbonyl]amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-(4-pyridin-2-ylpiperazin-1-yl)butyl,3-(3-pyridin-3-ylisoxazol-5-yl)propyl,2-{[(pyridin-3-ylamino)carbonothioyl]amino}ethyl,2-{[(dimethylamino)carbonyl]amino}ethyl, and2-{[(phenylamino)carbonyl]amino}ethyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino }ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, and4-methanesulfonylaminobutyl. In some embodiments (e.g., of Formulas IIthrough IX and LXXX), the above group from which R₁ is selected alsoincludes 3-amino-2,2-dimethyl-3-oxopropyl and 2,2-dimethyl-4-oxopentyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl, 2-(benzoylamino)ethyl, and4-methanesulfonylaminobutyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, 2-cyclohexylethyl,2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl,2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl, 2-(benzoylamino)ethyl,4-methanesulfonylaminobutyl, and 2-methylpropyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methylpropyl, 2-methanesulfonylethyl, and 4-methanesulfonylaminobutyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of 2-methylpropyl,2,2-dimethylpropyl, ethyl, and 4-[(morpholin-4-ylcarbonyl)amino]butyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of 2-methylpropyl,2,2-dimethylpropyl, and ethyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl and 2-methylpropyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is2-methylpropyl.

In some embodiments, R₁ is C₁₋₄ alkyl. In certain embodiments, R₁ isstraight chain C₁₋₄ alkyl. In certain embodiments, R₁ is branched C₁₋₄alkyl.

In some embodiments, R₁ is selected from the group consisting of methyl,ethyl, propyl, 2-methylpropyl, 2,2-dimethylpropyl, and butyl.

In some embodiments, R₁ is selected from the group consisting ofpent-4-ynyl and 2-phenylethyl. In certain embodiments, R₁ is2-phenylethyl.

In some embodiments, R₁ is selected from the group consisting of2-hydroxy-2-methylpropyl and 2-amino-2-methylpropyl. In certainembodiments, R₁ is 2-hydroxy-2-methylpropyl. In certain embodiments, R₁is 2-amino-2-methylpropyl.

In some embodiments, R₁ is selected from the group consisting of4-hydroxybutyl, 2-aminoethyl, 4-aminobutyl, 4-chlorobutyl, and4-acetoxybutyl.

In some embodiments, R₁ is C₁₋₄ alkyl-S(O)₂—C₁₋₄ alkylenyl.

In some embodiments, R₁ is phenyl—S(O)₂—C₁₋₄ alkylenyl.

In some embodiments, R₁ is selected from the group consisting of2-methanesulfonylethyl, 2-(propylsulfonyl)ethyl,4-(methylsulfonyl)butyl, and 3-(phenylsulfonyl)propyl.

In some embodiments, R₁ is C₁₋₄ alkyl-S(O)₂—C₁₄ alkyleneoxyC₁₋₄alkylenyl.

In some embodiments, R₁ is 2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl.

In some embodiments, R₁ is C₁₋₄ alkyl-S(O)₂—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is aryl-S(O)₂—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is diC₁₋₄ alkyl-N—S(O)₂—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is selected from the group consisting of4-methanesulfonylaminobutyl, 2-(benzenesulfonylamino)ethyl,2-(2-propanesulfonylamino)ethyl, and2-(dimethylaminosulfonylamino)ethyl. In certain embodiments, R₁ is4-methanesulfonylaminobutyl.

In some embodiments, R₁ is NH₂—C(O)-alkylenyl.

In some embodiments, R₁ is 3-amino-2,2-dimethyl-3-oxopropyl.

In some embodiments, R₁ is alkyl-C(O)-alkylenyl.

In some embodiments, R₁ is 2,2-dimethyl-4-oxopentyl.

In some embodiments, R₁ is hydrogen.

In some embodiments, R₁ is C₁₋₄ alkyl-C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is aryl-C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is heteroaryl-C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is selected from the group consisting of2-(benzoylamino)ethyl, 2-[(pyridin-3-ylcarbonyl)amino]ethyl, and2-(isobutyrylamino)ethyl.

In some embodiments, R₁ is C₁₋₆ alkyl-NH—C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is N(C₁₋₄ alkyl)₂-C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is aryl-NH—C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is heteroaryl-NH—C(R₆)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is heterocyclyl-C(O)—NH—C₁₋₄ alkylenyl.

In some embodiments, R₁ is selected from the group consisting of4-[(morpholin-4-ylcarbonyl)amino]butyl,2-{[(isopropylamino)carbonyl]amino}ethyl,2-{[(pyridin-3-ylamino)carbonothioyl]amino}ethyl,2-{[(pyridin-3-ylamino)carbonyl]amino}ethyl,2-{[(dimethylamino)carbonyl]amino}ethyl, and2-{[(phenylamino)carbonyl]amino}ethyl.

In some embodiments, R₁ is 2-methyl-2-[(methylsulfonyl)aminopropyl.

In some embodiments, R₁ is selected from the group consisting of2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-[(cyclopropylcarbonyl)amino]-2-methylpropyl,2-(isobutyrylamino)-2-methylpropyl, 2-methyl-2-(propionylamino)propyl,2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl,2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl,2-(acetylamino)-2-methylpropyl, 2-(benzoylamino)-2-methylpropyl,2-[(4-fluorobenzoyl)amino]-2-methylpropyl, and2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl.

In some embodiments, R₁ is2-{[(isopropylamino)carbonyl]amino]-2-methylpropyl.

In some embodiments, R₁ is selected from the group consisting of4-(aminosulfonyl)butyl, 4-[(methylamino)sulfonyl]butyl, and4-[(dimethylamino)sulfonyl]butyl.

In some embodiments, R₁ is heteroarylC₁₋₄ alkylenyl wherein heteroarylis unsubstituted or substituted by a substituent selected from the groupconsisting of aryl, heteroaryl, and alkyl.

In some embodiments, R₁ is selected from the group consisting of3-(3-methylisoxazol-5-yl)propyl, 3-(3-isopropylisoxazol-5-yl)propyl,3-(3-phenylisoxazol-5-yl)propyl, 3-(3-pyridin-3-ylisoxazol-5-yl)propyl,4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl, and4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl.

In some embodiments, R₁ is 4-(4-pyridin-2-ylpiperazin-1-yl)butyl.

Each of the embodiments for R₁ described above can be combined with oneor more embodiments for R₂ described below. Each of the resultingcombinations is an embodiment.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of —R₄, —X—R₄, —X—Y—R₄, and —X—R₅;wherein:

-   -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of —O—, —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,        —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈), —CH(—N(—O—R₈)-Q-R₄)—,    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7. In certain of these embodiments, the above group        from which Y is selected also includes —C(═N—O—R₈)—NH—. In        certain of these embodiments (e.g., of Formulas II through IX        and LXXX), Y is selected from the group consisting of —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   and R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl. In certain        of these embodiments (e.g., of Formulas II through IX and LXXX),        Y is selected from the group consisting of —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, and arylalkylenyl; and Q is selected from the        group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—,        —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of —R₄, —X—R₄, and —X—Y-R₄; wherein:

-   -   X is alkylene that is optionally terminated by arylene or        heterocyclylene;    -   Y is selected from the group consisting of —S(O)₂—, —C(O)—,        —C(O)—O—, —N(R₈)-Q-, —C(O)—N(R₈)—, and    -   R₄ is selected from the group consisting of hydrogen, alkyl,        aryl, arylalkylenyl, aryloxyalkylenyl, heterocyclyl, and        heteroaryl, wherein the alkyl, aryl, aryloxyalkylenyl, and        heterocyclyl groups can be unsubstituted or substituted by one        or more substituents independently selected from the group        consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl,        haloalkoxy, halogen, nitro, hydroxy, cyano, aryl, aryloxy,        heteroaryl, heterocyclyl, and in the case of heterocyclyl, oxo;    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is in selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl; and    -   Q is selected from the group consisting of a bond, —C(O)—,        —S(O)₂—, —C(R₆)—N(R₈)—, and —S(O)₂—N(R₈)—.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ is—R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ is—X—R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ is—X—Y—R₄.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of hydrogen, alkyl, arylalkylenyl,alkoxyalkylenyl, and hydroxyalkylenyl. In certain embodiments, R₂ isselected from the group consisting of hydrogen, alkyl, arylalkylenyl,and alkoxyalkylenyl. In certain embodiments, R₂ is selected from thegroup consisting of hydrogen, alkyl, and alkoxyalkylenyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of hydrogen, C₁₋₅ alkyl, C₁₋₄alkoxyC₁₋₄ alkylenyl, hydroxyC₁₋₄ alkylenyl, and arylC₁₋₄ alkylenylwherein aryl is unsubstituted or substituted by one or more substituentsselected from the group consisting of chloro, fluoro, methoxy, methyl,cyano, and methoxycarbonyl.

In some embodiments, R₂ is selected from the group consisting ofhydrogen, C₁₋₅ alkyl, C₁₋₄ alkoxyC₁₋₄ alkylenyl, and arylC₁₋₄ alkylenylwherein aryl is unsubstituted or substituted by one or more substituentsselected from the group consisting of chloro, fluoro, methoxy, methyl,cyano, and methoxycarbonyl.

In some embodiments, R₂ is selected from the group consisting ofhydrogen, C₁₋₄ alkyl, and C₁₋₄ alkoxyC₁₋₄ alkylenyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of hydrogen, methyl, ethyl, propyl,butyl, 2-methoxyethyl, 2-hydroxyethyl, and benzyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of hydrogen, methyl, ethyl, propyl,butyl, 2-methoxyethyl, and benzyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of hydrogen, methyl, ethyl, propyl,butyl, and benzyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of methyl, ethyl, propyl, butyl, andbenzyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of methyl, ethyl, propyl, and butyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methoxyethyl, and 2-hydroxyethyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₂ ismethyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl. In some embodiments (e.g., of Formulas IIthrough IX and LXXX), the above group from which R₁ is selected alsoincludes 3-amino-2,2-dimethyl-3-oxopropyl and 2,2-dimethyl-4-oxopentyl.In certain of these embodiments, m and n are 0.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of methyl, ethyl, propyl, butyl,2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl, 2-(benzoylamino)ethyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl,and benzyl. In certain of these embodiments, m and n are 0.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ isselected from the group consisting of 2-methylpropyl,2,2-dimethylpropyl, ethyl, and 4-[(morpholin-4-ylcarbonyl)amino]butyl;and R₂ is selected from the group consisting of methyl, ethyl, propyl,butyl, and benzyl. In certain of these embodiments m and n are 0. Incertain of these embodiments, R₁ is selected from the group consistingof 2-methylpropyl, 2,2-dimethylpropyl, and ethyl.

In some embodiments (e.g., of Formulas II through IX and LXXX), R₁ is2-hydroxy-2-methylpropyl, and R₂ is selected from the group consistingof methyl, ethyl, propyl, butyl, 2-methoxyethyl, and 2-hydroxyethyl.

In some embodiments (e.g., of Formulas III through VII), R₁ is selectedfrom the group consisting of methyl, ethyl, propyl, butyl,2-methylpropyl, 2-methanesulfonylethyl, and 4-methanesulfonylaminobutyl;and R₂ is selected from the group consisting of hydrogen, methyl, ethyl,propyl, butyl, and benzyl. In certain of these embodiments, m and n are0.

In some embodiments (e.g., of Formulas II through VII), R₁ is2-methylpropyl; and R₂ is selected from the group consisting of methyl,ethyl, propyl, and butyl. In certain of these embodiments, m and n are0.

In some embodiments of Formula VIII, R₁ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methylpropyl,2,2-dimethylpropyl, 2-cyclohexylethyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, butyl, 2-methoxyethyl,and 2-hydroxyethyl. In certain of these embodiments, n is 0.

In some embodiments of Formula VIII, R₁ is selected from the groupconsisting of methyl, 2-cyclohexylethyl, 2,2-dimethylpropyl,2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl,2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl, 2-(benzoylamino)ethyl,4-methanesulfonylaminobutyl, and 2-methylpropyl; and R₂ is selected fromthe group consisting of methyl, ethyl, propyl, and butyl. In certain ofthese embodiments, n is 0.

In some embodiments of Formula VIII, R₁ is selected from the groupconsisting of methyl and 2-methylpropyl; R₂ is methyl. In certain ofthese embodiments, n is 0.

In some embodiments of Formula IX, R₁ is selected from the groupconsisting of methyl and 2-methylpropyl; and R₂ is methyl. In certain ofthese embodiments, R_(A2) and R_(B2) are each methyl.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of -Z-R₄, -Z-X—R₄, -Z-X—Y—R₄, -Z-X—Y—X—Y—R₄,and -Z-R₅ wherein:

-   -   X is selected from the group consisting of alkylene, alkenylene,        alkynylene, arylene, heteroarylene, and heterocyclylene wherein        the alkylene, alkenylene, and alkynylene groups can be        optionally interrupted or terminated by arylene, heteroarylene        or heterocyclylene and optionally interrupted by one or more —O—        groups;    -   Y is selected from the group consisting of —O—, —S(O)₀₋₂—,        —S(O)₂—N(R)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈), —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,        —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,    -   Z is a bond or —O—;    -   R₄ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,        alkylarylenyl, heteroaryl, heteroarylalkylenyl,        heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl        wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,        aryloxyalkylenyl, alkylarylenyl, heteroaryl,        heteroarylalkylenyl, heteroaryloxyalkylenyl,        alkylheteroarylenyl, and heterocyclyl groups can be        unsubstituted or substituted by one or more substituents        independently selected from the group consisting of alkyl,        alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,        hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,        heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,        amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and        in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;    -   R₅ is selected from the group consisting of    -   R₆ is selected from the group consisting of ═O and ═S;    -   R₇ is C₂₋₇ alkylene;    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and        heteroarylalkylenyl;    -   R₉ is selected from the group consisting of hydrogen and alkyl;    -   R₁₀ is C₃₋₈ alkylene;    -   A is selected from the group consisting of —O—, —C(O)—,        —S(O)₀₋₂—, and —N(R₄)—;    -   A′ is selected from the group consisting of —O—, —S(O)₀₋₂—,        —N(-Q-R₄)—, and —CH₂—;    -   Q is selected from the group consisting of a bond, —C(R₆)—,        —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,        —C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—;    -   V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,        —N(R₈)—C(R₆)—, and    -   —S(O)₂—;    -   W is selected from the group consisting of a bond, —C(O)—, and        —S(O)₂—; and    -   a and b are independently integers from 1 to 6 with the proviso        that a+b is ≦7. In certain of these embodiments, the above group        from which Y is selected also includes —C(═N—O—R₈)—NH—. In        certain of these embodiments (e.g., of Formulas II through VII),        Y is selected from the group consisting of —S(O)₀₋₂—,        —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,        —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   and R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl. In certain        of these embodiments (e.g., of Formulas II through VII), Y is        selected from the group consisting of —S(O)₀₋₂—, —S(O)₂—N(R₈)—,        —C(R₆)—, —C(R₆)—O—, —O—C(R₆, —O—C(O)—O—, —N(R₈)-Q-,        —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,    -   R₅ is selected from the group consisting of    -   R₈ is selected from the group consisting of hydrogen, alkyl,        alkoxyalkylenyl, and arylalkylenyl; and Q is selected from the        group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—,        —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—.

In some embodiments (e.g., of Formulas II through VII), R₃ is at the7-position of the pyrazoloquinoline or pyrazolonaphthyridine.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of alkylsulfonylalkyleneoxy,alkylsulfonylaminoalkyleneoxy, alkylcarbonylaminoalkyleneoxy, aryl,arylalkyleneoxy, heteroaryl, heteroarylalkyleneoxy, heterocyclyl, andheterocyclylalkyleneoxy; wherein aryl and heteroaryl are unsubstitutedor substituted by one or more substituents selected from the groupconsisting of alkyl, alkoxy, hydroxyalkyl, halogen,heterocyclylcarbonyl, and dialkylaminocarbonyl; and wherein heterocyclylis unsubstituted or substituted by one or more substitutents selectedfrom the group consisting of alkylsulfonyl, alkylcarbonyl, and oxo.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of aryl, arylalkyleneoxy,heteroarylalkyleneoxy, and heteroaryl, wherein aryl, arylalkyleneoxy,and heteroaryl are unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl, hydroxyalkyl,and halogen, m is 1, and n is 0.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of aryl, arylalkyleneoxy, and heteroaryl,wherein aryl, arylalkyleneoxy, and heteroaryl are unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of alkyl and halogen.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of phenyl, benzyloxy, 3-furyl, pyridin-3-yl,5-(hydroxymethyl)pyridin-3-yl, 6-chloropyridin-3-yl,6-fluoropyridin-3-yl, 6-methylpyridin-3-yl, 3-quinolin-3-yl,thiazol-4-ylmethoxy, p-toluyl, (4-chlorobenzyl)oxy, and(4-methylbenzyl)oxy.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of phenyl, benzyloxy, 3-furyl, pyridin-3-yl,p-toluyl, (4-chlorobenzyl)oxy, and (4-methylbenzyl)oxy.

In some embodiments (e.g., of Formulas II through VII), R₃ is selectedfrom the group consisting of benzyloxy, (4-chlorobenzyl)oxy,(4-methylbenzyl)oxy, thiazol4-ylmethoxy, phenyl, p-toluyl,2-ethoxyphenyl, 3-(morpholine-4-carbonyl)phenyl,3-(N,N-dimethylaminocarbonyl)phenyl, 3-furyl, pyridin-3-yl, pyridin4-yl,6-chloropyridin-3-yl, 6-fluoropyridin-3-yl, 6-methylpyridin-3-yl,5-(hydroxymethyl)pyridin-3-yl, and quinolin-3-yl.

In some embodiments (e.g., of Formulas II through VII), R₃ ispyridin-3-yl, pyridin-4-yl, 6-fluoropyridin-3-yl,5-(hydroxymethyl)pyridin-3-yl, quinolin-3-yl, 2-ethoxyphenyl, or3-(morpholine-4-carbonyl)phenyl.

In some embodiments (e.g., of Formulas II through VII), R₃ is2-oxo-1,3-oxazolidin-3-yl.

In some embodiments (e.g., of Formulas II through VII), R₃ is1,3-thiazol-4-ylmethoxy, (1-methyl-1H-imidazol-2-yl)methoxy, orpyridin-3-ylmethoxy.

In some embodiments (e.g., of Formulas II through VII), R₃ is2-pyrrolidin-1-ylethoxy, 2-(2-oxopyrrolidin-1-yl)ethoxy,2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy, 2-morpholin-4-ylethoxy,3-pyrrolidin-1-ylpropoxy, 3-(2-oxopyrrolidin-1-yl)propoxy,3-(1,1-dioxidoisothiazolidin-2-yl)propoxy, 3-morpholin-4-ylpropoxy,2-morpholin-4-yl-2-oxoethoxy, and

wherein R is alkylsulfonyl or alkylcarbonyl.

In some embodiments (e.g., of Formulas II through VII), R₃ isalkyl-S(O)₂—NH—(CH₂)₂₋₃—O—, alkyl-S(O)₂—(CH₂)₂₋₃—O—, oralkyl-C(O)—NH—(CH₂)₂₋₃—O—.

In some embodiments (e.g., of Formulas II through VII), R₁ is2-hydroxy-2-methylpropyl, R₂ is 2-hydroxyethyl, and R₃ is phenyl whichis substituted by one or two substituents independently selected fromchloro and fluoro.

In some embodiments, including any one of the above embodiments whichparticularly defines R₃, R₃ is at the 7-position of thepyrazoloquinoline or pyrazolonaphthyridine. In certain of theseembodiments, m is 1, and n is 0.

In some embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo. In certain of these embodiments, R₄ is alkyl,aryl, or heteroaryl.

In some embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkylenyl,alkynyl, arylalkylenyl, and arylalkenylenyl, wherein the alkyl, aryl,arylalkylenyl, heterocyclyl, heteroaryl, and heteroarylalkylenyl groupscan be unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, alkoxy,haloalkyl, haloalkoxy, halogen, hydroxy, cyano, aryl, aryloxy,heteroaryl, heterocyclyl, amino, dialkylamino, and in the case of alkyland heterocyclyl, oxo.

In some embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkylenyl,alkynyl, and arylalkenylenyl, wherein the alkyl, aryl, heterocyclyl,heteroaryl, and heteroarylalkylenyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,hydroxy, cyano, aryl, aryloxy, heteroaryl, heterocyclyl, amino,dialkylamino, and in the case of alkyl and heterocyclyl, oxo.

In some embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heterocyclyl,and heteroaryl, wherein the alkyl, aryl, aryloxyalkylenyl, andheterocyclyl groups can be unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,cyano, aryl, aryloxy, heteroaryl, heterocyclyl, and in the case ofheterocyclyl, oxo.

In some embodiments, R₄ is alkyl, aryl, or heteroaryl. In certainembodiments, R₄ is alkyl. In certain embodiments, R₄ is aryl. In certainembodiments, R₄ is heteroaryl.

In some embodiments, R₅ is selected from the group consisting of

In some embodiments, R₅ is selected from the group consisting of

In some embodiments, R₅ is selected from the group consisting of

In some embodiments, R₆ is selected from the group consisting of =O and=S. In certain embodments, R₆ is =O. In certain embodiments, R₆ is =S.

In some embodiments, R₇ is C₂₋₇ alkylene. In certain embodiments, R₇ isC₃₋₄ alkylene.

In some embodiments, R₈ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl. In certain embodiments, R₈ is selected from thegroup consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl,and arylalkylenyl. In certain embodiments, R₈ is selected from the groupconsisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl. Incertain embodiments, R₈ is hydrogen, alkyl, or hydroxyalkylenyl. Incertain embodiments, R₈ is hydrogen. In certain embodiments, R₈ isalkyl.

In some embodiments, R₉ is selected from the group consisting ofhydrogen and alkyl. In certain embodiments, R₉ is alkyl. In certainembodiments, R₉ is hydrogen.

In some embodiments, R₁₀ is C₃₋₈ alkylene. In certain embodiments, R₁₀is C₄₋₅ alkylene.

In some embodiments, A is selected from the group consisting of —O—,—C(O)—, —S(O)₀₋₂—, and —N(R₄)—. In certain embodiments, A is selectedfrom the group consisting of —O—, —C(O)—, and —N(R₄)—. In certainembodiments, A is —O—.

In some embodiments, A′ is selected from the group consisting of —O—,—S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—.

In some embodiments, Q is selected from the group consisting of a bond,—C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,—C(R₆)—O—, —C(R₆)—S—, and —C(R₆)—N(OR₉)—. In certain embodiments, Q isselected from the group consisting of a bond, —C(R₆)—, —-C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—.In certain embodiments, Q is selected from the group consisting of abond, —C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(O)—O—, and—C(O)—S—. In certain embodiments, Q is selected from the groupconsisting of a bond, —C(O)—, —S(O)₂—, —C(R₆)—N(R₈)—, and —S(O)₂—N(R₈)—.In certain embodiments, Q is selected from the group consisting of abond, —C(R₆)—, —S(O)₂—, and —C(R₆)—N(R₈)—W—. In certain embodiments, Qis selected from the group consisting of a bond, —C(O)—, —S(O)₂—, and—C(O)—N(R₈)—.

In some embodiments, V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—. In certain embodiments, V is—C(R₆)—. In certain embodiments, V is —N(R₈)—C(R₆)—.

In some embodiments, W is selected from the group consisting of a bond,—C(O)—, and —S(O)₂—. In certain embodiments, W is selected from thegroup consisting of a bond and —C(O)—. In certain embodiments, W is abond.

In some embodiments, X is selected from the group consisting ofalkylene, alkenylene, alkynylene, arylene, heteroarylene, andheterocyclylene wherein the alkylene, alkenylene, and alkynylene groupscan be optionally interrupted or terminated by arylene, heteroarylene orheterocyclylene and optionally interrupted by one or more —O— groups.

In some embodiments, X is alkylene that is optionally interrupted orterminated by heterocyclylene and optionally interrupted by one —O—group.

In some embodiments, X is alkylene that is optionally terminated byarylene or heterocyclylene.

In some embodiments, X is alkylene that is optionally interrupted orterminated by heterocyclylene.

In some embodiments, X is alkylene. In certain embodiments, X is C₁₋₄alkylene.

In some embodiments, X¹ is selected from the group consisting ofalkylene and arylene. In certain embodiments, X¹ is alkylene. In certainembodiments, X¹ is C₁₋₄ alkylene. In certain embodiments, X¹ is arylene.

In some embodiments, Y is selected from the group consisting of —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—,

In some embodiments, the above group from which Y is selected alsoincludes —C(═N—O—R₈)—NH—.

In some embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

In some embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

In some embodiments, Y is selected from the group consisting of —S(O)₂—,—S(O)₂—N(R₈)—, —C(O)—, —C(O)—O—, —O—C(O)—, —N(R₈)-Q-, —C(O)—N(R₈)—,

In some embodiments, Y is selected from the group consisting of —S(O)₂—,—C(O)—, —C(O)—O—, —N(R₈)-Q-, —C(O)—N(R₈)—, and

In some embodiments, Y is —N(R₈)—C(O)—, —N(R₈)—S(O)₂—,—N(R₈)—C(O)—N(R₈)—, —N(R₈)—C(S)—N(R₈)—, —N(R₈)—S(O)₂—(R₈)—, or

In some embodiments, Y is —N(R₈)—C(O)—, —N(R₈)—S(O)₂—,—N(R₈)—C(O)—N(R₈)—, or

In some embodiments, Y is —N(R₈)—C(O)—, —N(R₈)—S(O)₂—, —S(O)₂—N(R₈)—, or—N(R₈)—C(O)—N(R₈)—. In certain embodiments, Y is —N(R₈)—C(O)—. Incertain embodiments, Y is —N(R₈)—S(O)₂—. In certain embodiments, Y is—S(O)₂—N(R₈)—. In certain embodiments, Y is —N(R₈)—C(O)—N(R₈)—.

In some embodiments, Y¹ is selected from the group consisting of —S—,—C(O)—, —C(O)—O—, —C(O)—N(R₈)—, —S(O)₂—N(R₈)—, and —N(R₈)—C(O)—. In someembodiments, Y¹ is selected from the group consisting of —S—, —C(O)—,and —C(O)—O—.

In some embodiments, Z is a bond or —O—. In certain embodiments, Z is abond. In certain embodiments, Z is —O—.

In some embodiments, a and b are independently integers from 1 to 6 withthe proviso that a+b is ≦7. In some embodiments, a and b are each theinteger 2.

In some embodiments (e.g., of Formulas III-VII), n is 0, or m is 0.

In some embodiments (e.g., of Formulas III-VII), m and n are 0.

In some embodiments (e.g., of Formulas III-VII), m is 0, and n is 1.

In some embodiments (e.g., of Formulas III-VII), m is 1, and n is 0.

In some embodiments (e.g., of Formula VIII), n is 0.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt of any one of Formulas I, Ia, II, III, IV, V, VI, VII, VIII, IX,LXXX, II-1, or any one of the above embodiments in combination with apharmaceutically acceptable carrier.

In some embodiments, the present invention provides a method of inducingcytokine biosynthesis in an animal comprising administering an effectiveamount of a compound or salt of any one of Formulas I, Ia, II, III, IV,V, VI, VII, VIII, IX, LXXX, II-1, or any one of the above embodiments oradministering any one of the above pharmaceutical compositions to theanimal.

In some embodiments, the present invention provides a method of treatinga viral disease in an animal in need thereof comprising administering atherapeutically effective amount of a compound or salt of any one ofFormulas I, Ia, III, III, IV, V, VI, VII, VIII, IX, LXXX, II-1, or anyone of the above embodiments or administering any one of the abovepharmaceutical compositions to the animal.

In some embodiments, the present invention provides a method of treatinga neoplastic disease in an animal in need thereof comprisingadministering a therapeutically effective amount of a compound or saltof any one of Formulas I, Ia, II, III, IV, I, V, VI, VII, VIII, IX,LXXX, II-1, or any one of the above embodiments or administering any oneof the above pharmaceutical compositions to the animal.

Preparation of Compounds

Compounds of the invention can be prepared according to Reaction SchemeI, where R, R₁, R₂, and n are defined as above. Ketoesters of Formula Xin Reaction Scheme I and their sodium salts are known and can beprepared from a variety of ketones using conventional methods, such asthe Claisen condensation, Claisen, L., Berichte, 42, 59 (1909).

Numerous functionalized ketones useful as Claisen condensation startingmaterials are commercially available; others can be prepared by knownmethods. For example, tert-butyl 1,1-dimethyl-3-oxobutylcarbamate, alsocalled (1,1-dimethyl-3-oxobutyl)carbamic acid tert-butyl ester, has beenreported, Peschke, B. et al, Eur. J. Med. Chem., 34, pp. 363-380,(1999). In another example, 4-(propylthio)butan-2-one can be prepared bycombining 1-propanethiol and 4-chloro-2-butanone at ambient temperaturein the presence of sodium hydride in a suitable solvent such astetrahydrofuran (THF) and isolating the product using conventionalmethods. In a third example, a Michael addition can be carried out withphenyl vinyl sulfone and a carbanion generated from methyl acetoacetateand sodium methoxide. The resulting Michael adduct can be decarboxylatedunder acidic conditions, for example hydrochloric acid in methanol, toprovide 5-(phenylsulfonyl)pentan-2-one.

In step (1) of Reaction Scheme I, a sodium salt of a compound of FormulaX reacts with a hydrazine of Formula R₂NHNH₂ to provide a pyrazolecarboxylate of Formula XI. The reaction is conveniently carried out byslowly adding the hydrazine to a solution of the salt of a compound ofFormula X in a suitable solvent such as acetic acid. The reaction can becarried out at ambient temperature, and the product can be isolatedusing conventional methods.

If step (1) is carried out using hydrazine, the resulting pyrazolecarboxylate of Formula XI where R₂ is hydrogen can be alkylated usingknown synthetic methods, Auwers, K. v., Hollman, H., Berichte, 59, 606(1926), to provide a pyrazole carboxylate of Formula XI where R₂ isdefined as above. The alkylation is conveniently carried out by treatinga solution of the pyrazole carboxylate of Formula XI, where R₂ ishydrogen, with a base such as sodium ethoxide followed by an alkylatingagent of Formula R₂-Halide. The reaction is run in a suitable solventsuch as ethanol and can be carried out at an elevated temperature, forexample, the reflux temperature of the solvent, or at ambienttemperature. Numerous reagents of Formula R₂-Halide are commerciallyavailable; others can be prepared using known synthetic methods. Thepyrazole carboxylate of Formula XI can be isolated from the reaction andseparated from its isomer using conventional methods.

In step (2) of Reaction Scheme I, the ester group of a pyrazolecarboxylate of Formula XI is converted to an amide. The amination isconveniently carried out by adding ammonium hydroxide to the pyrazolecarboxylate of Formula XI in a suitable solvent such as methanol andheating at an elevated temperature such as 100° C. The reaction can becarried out in a pressure vessel. The resulting pyrazole carboxamide ofFormula XII can be isolated using conventional methods.

Alternatively, step (2) can be carried out by first hydrolyzing apyrazole carboxylate of Formula XI to a carboxylic acid and thenconverting the carboxylic acid to an amide. The ester hydrolysis can becarried out under basic conditions by combining a pyrazole carboxylateof Formula XI with lithium hydroxide or sodium hydroxide in water and ina suitable solvent such as methanol or ethanol. The reaction can becarried out at ambient temperature, and the carboxylic acid product canbe isolated using conventional methods. The conversion of the carboxylicacid to a pyrazole carboxamide of Formula XII can be carried out byfirst treating the carboxylic acid with oxalyl chloride at ambienttemperature in a suitable solvent such as dichloromethane to generate anacid chloride, which can then be treated with ammonium hydroxide at asub-ambient temperature such as 0° C. Alternatively, the conversion ofthe carboxylic acid to a pyrazole carboxamide of Formula XII can becarried out under coupling conditions by adding 1-hydroxybenzotriazoleand 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to asolution of the carboxylic acid in a suitable solvent such asN,N-dimethylformamide (DMF) at ambient temperature and then addingconcentrated ammonium hydroxide. The product can be isolated usingconventional methods.

In step (3) of Reaction Scheme I, a pyrazole carboxamide of Formula XIIis dehydrated to a pyrazole carbonitrile of Formula XIII. Suitabledehydrating agents include thionyl chloride, trifluoroacetic anhydride,and phosphorous oxychloride. The reaction is conveniently carried out bytreating the pyrazole carboxamide of Formula XII with phosphorousoxychloride and heating the reaction at an elevated temperature such as90° C. The reaction can also be carried out by combining the pyrazolecarboxamide of Formula XII with trifluoroacetic anhydride in thepresence of a base such as triethylamine and in a suitable solvent suchas dichloromethane. The reaction can be carried out at ambienttemperature or at a sub-ambient temperature such as 0° C. The productcan be isolated using conventional methods.

In step (4) of Reaction Scheme I, a pyrazole carbonitrile of Formula XIIis brominated to provide a bromo-substituted pyrazole carbonitrile ofFormula XIV. The bromination is conveniently carried out by addingbromine to a solution of the pyrazole carbonitrile of Formula XIII andpotassium acetate in acetic acid. The reaction can be carried out atambient temperature, and the product can be isolated using conventionalmethods.

In step (5) of Reaction Scheme I, a bromo-substituted pyrazolecarbonitrile of Formula XIV undergoes a transition-metal catalyzed crosscoupling reaction with a reagent of Formula XV to form apyrazole-substituted aniline of Formula XVI. Reagents of Formula XV,where M is, for example, —B(OH)₂, —B(O-alkyl)₂, —Sn(alkyl)₃, and —Zn—Halide, are known to undergo coupling reactions. Several reagents ofFormula XV are commercially available; others can be prepared usingknown synthetic methods. For example, tert-butoxycarbonyl(Boc)-protected anilines undergo directed ortho metalation in thepresence of butyllithium reagents. The resulting organolithiumintermediate reacts with electrophiles such as B(O-alkyl)₃ andClSn(alkyl)₃ to provide compounds of Formula XV, where M is —B(O-alkyl)₂or —B(OH)₂ and —Sn(alkyl)₃, respectively, after removal of the Bocprotecting group.

In step (5), a Suzuki coupling reaction is conveniently carried out byheating a mixture of the bromo-substituted pyrazole carbonitrile ofFormula XIV, palladium (II) acetate, triphenylphosphine, and a boronreagent of Formula XV, where M is —B(OH)₂ or —B(O-alkyl)₂, in thepresence of a base such as sodium carbonate. The reaction is carried outin a suitable solvent or solvent mixture such as n-propanol:water andcan be heated at an elevated temperature such as 100° C. The product canbe isolated using conventional methods.

In step (6) of Reaction Scheme I, the amine and nitrile functionalitiesof a pyrazole-substituted aniline of Formula XVI react under acidicconditions to form a pyrazolo[3,4-c]quinoline of Formula XVII, asubgenus of Formulas I, II, III, and Ia. The intramolecular addition isconveniently carried out by stirring acetyl chloride in ethanol andadding the resulting acidic solution to the pyrazole-substituted anilineof Formula XVI. The reaction is then heated at reflux to provide thepyrazolo[3,4-c]quinoline of Formula XVII. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Alternatively, in steps (5) and (6) of Reaction Scheme I, abromo-substituted pyrazole carbonitrile of Formula XIV undergoes aSuzuki coupling with a reagent of Formula XLII.

Some compounds of Formula XLII are known or can be prepared by knownsynthetic methods; see, Rocca, P. et al, Tetrahedron, 49, pp. 49-64(1993). The Suzuki coupling reaction can be carried out according to themethod described above. The resulting pivaloylamino-substituted compoundundergoes a base-promoted intramolecular cyclization in step (6) ofReaction Scheme I and subsequent cleavage of the pivaloyl group toprovide a pyrazolo[3,4-c]quinoline of Formula XVII. The reaction isconveniently carried out by heating the pivaloylamino-substitutedcoupling product with potassium tert-butoxide in a suitable solvent suchas ethanol at an elevated temperature such as the reflux temperature ofthe solvent. The product or pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

For some embodiments, compounds in Reaction Scheme I can be furtherelaborated using conventional synthetic methods. For example, R₁ can bea 2-[(tert-butoxycarbonyl)amino]-2-methylpropyl group if tert-butyl1,1-dimethyl-3-oxobutylcarbamate is used as the starting ketone to makethe ketoester of Formula X. The tert-butoxycarbonyl group is removedunder the acidic cyclization conditions described in step (6) to providea 2-amino-2-methylpropyl group, which can be converted to an amide, asulfonamide, a sulfamide, or a urea using the methods described below instep (11) of Reaction Scheme VII.

In another example, an olefin-containing R₁ group may be oxidized to anepoxide by conventional methods. The oxidation is conveniently carriedout prior to step (4) of Reaction Scheme I by adding3-chloroperoxybenzoic acid to a solution of a pyrazole carbonitrile ofFormula XIII, which contains an olefin substituent, in a suitablesolvent such as dichloromethane. The reaction may be carried out atambient temperature, and the product can be isolated by conventionalmethods. The epoxide can be opened during the bromination in step (4) bycombining the compound of Formula XIII, which contains an epoxidesubstituent, with two equivalents of bromine in acetic acid at ambienttemperature to provide a compound of Formula XIV substituted at R₁ witha vicinal bromohydrin. The bromohydrin may then be reduced under freeradical conditions to provide a compound of Formula XIV substituted witha hydroxyalkyl group. The reduction may be carried out by addingtributyltin hydride and azobisisobutyronitrile at ambient temperature toa bromohydrin-substituted compound of Formula XIV in a suitable solventsuch as toluene. The product may be isolated by conventional methods andthen subjected to steps (5) and (6) of Reaction Scheme I. Using thesemethods an R₁ 2-methylpropenyl group can be converted into a2-hydroxy-2-methylpropyl group.

A hydroxy group introduced at the RI position according to the abovemethod can be treated with sodium hydride to form an alkoxide, which isreacted with a vinyl sulfone of Formula CH₂═CH—S(O)₂—R₄ to provide acompound in which RI is —X—Y—P₄, wherein Y is

—SO₂—. The reaction can be carried out by adding catalytic sodiumhydride dispersed in mineral oil to a solution of a compound of FormulaXIV, wherein RI has hydroxy group, and a vinyl sulfone in a suitablesolvent such DMF or tetrahydrofuran. The reaction can be run at ambienttemperature. The product or a pharmaceutically acceptable salt thereofcan be isolated by conventional methods and then subjected to steps (5)and (6) of Reaction Scheme I. Many vinyl sulfones are commerciallyavailable or can be prepared using known synthetic methods. Thesemethods can be used to provide a compound of Formula XVII, wherein R₁ isa 2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl group.

In another example, R₁ can be —X—Y—R₄, wherein Y is —S—. The thioethergroup may be oxidized to a sulfone prior to step (2) of Reaction SchemeI to provide a compound where R₁ is —X—Y—R₄ and Y is —SO₂—. Theoxidation is conveniently carried out by adding 3-chloroperoxybenzoicacid to a solution of a pyrazole carboxylate of Formula XI in a suitablesolvent such as dichloromethane or chloroform. The product may beisolated by conventional methods and then subjected to steps (2) through(6) of Reaction Scheme I.

Pyrazolo[3,4-c]naphthyridines of the invention can be prepared accordingto Reaction Scheme II, where R, R₁, R₂, and n are as defined above. Instep (1) of Reaction Scheme II, a bromo-substituted pyrazolecarbonitrile of Formula XIV undergoes a transition-metal catalyzed crosscoupling reaction with a reagent of Formula XVIII or a positional isomerthereof, where M is as defined above, to form a pyrazole-substitutedaminopyridine of Formula XIX. Reagents of Formula XVIII and its isomerscan be prepared using known methods, for example, by directed orthometalation of Boc-protected aminopyridines and subsequent electrophilicsubstitution. Alternatively, for some isomers, halogen-lithium exchangeand subsequent electrophilic substitution can be used. For example,halogen-lithium exchange can be carried out on a 2-bromopyridine thathas a protected amino group in the 3-position; subsequent electrophilicsubstitution with tributyltin chloride and deprotection of the aminogroup provides 3-amino-2-tri-n-butylstannylpyridine, a useful reagentfor step (1) of Reaction Scheme II. The coupling reaction in step (1) ofReaction Scheme II can be carried out as described for step (5) ofReaction Scheme I.

In step (2) of Reaction Scheme II, the amine and nitrile functionalitiesof a pyrazole-substituted aminopyridine of Formula XIX react underacidic conditions to form a pyrazolo[3,4-c]naphthyridine of Formula XX,a subgenus of Formulas I, II, VI, and Ia, or an isomer thereof. Step (2)of Reaction Scheme II can be carried out as described for step (6) ofReaction Scheme I, and the product can be isolated by conventionalmethods.

Compounds of the invention can also be prepared according to ReactionScheme III, where n is defined as above and R_(a), R_(1a), and R_(2a)are subsets of R, R₁, and R₂ as defined above that do not include thosesubstituents which one skilled in the art would recognize as beingsusceptible to oxidation in step (5). These susceptible substituentsinclude —S— or heteroaryl groups.

Acetals of Formula XXI are reported in the literature and can beprepared using known synthetic methods, Royals, E. E., Robinson, A. G.III, J. Am. Chem. Soc., 78, 4161 (1956). For example, a ketone ofFormula CH₃C(O)R_(1a) can be condensed with ethyl diethoxyacetate underClaisen condensation conditions to provide an acetal of Formula XXI. Thereaction is conveniently carried out by adding sodium tert-butoxide to asolution of ethyl diethoxyacetate and the ketone of FormulaCH₃C(O)R_(1a) in ethanol and heating the reaction at reflux. Numerousketones of Formula CH₃C(O)R_(1a) are commercially available. Others canbe readily prepared using known synthetic methods. Amido ketones can beprepared according to the literature procedure, Ritter, J. J. andMinieri, P. P., J. Am. Chem. Soc., 70, 4045, (1948) by adding a nitrileof Formula R₄—CN to an α,β-unsaturated ketone under acidic conditions.

In step (1) of Reaction Scheme III, an acetal of Formula XXI is reactedwith a hydrazine of Formula R_(2a)—NH—NH₂ to provide a pyrazole ofFormula XXII. The reaction is conveniently carried out by slowly addingthe hydrazine to a solution of an acetal of Formula XXI in a suitablesolvent such as ethanol. The reaction can be run at ambient temperature,and the product can be isolated using conventional methods.

In step (2) of Reaction Scheme III, the acetal in the pyrazole ofFormula XXII is converted to an aldehyde under acidic conditions. Thereaction is conveniently carried out by treating the acetal-substitutedpyrazole of Formula XXII with hydrochloric acid in a suitable solventsuch as tetrahydrofuran. The reaction can be carried out at ambienttemperature to provide an aldehyde-substituted pyrazole of FormulaXXIII. The product can be isolated using conventional methods.

In step (3) of Reaction Scheme III, a pyrazole of Formula XXIII isbrominated to provide a bromo-substituted pyrazole of Formula XXIV. Thereaction can be carried out as described in step (4) of Reaction SchemeI.

In step (4) of Reaction Scheme III, a bromo-substituted pyrazole ofFormula XXIV undergoes a transition-metal catalyzed cross couplingreaction with a reagent of Formula XV, where M is defined as above. Thereaction is conveniently carried out using the Suzuki reactionconditions described in step (5) of Reaction Scheme I. Under thesereaction conditions, intramolecular condensation of the amine with thealdehyde group takes place to form a pyrazolo[3,4-c]quinoline of FormulaXXV. The product can be isolated using conventional methods.

In step (5) of Reaction Scheme III, a pyrazolo[3,4-c]quinoline ofFormula XXV is oxidized to provide a pyrazolo[3,4-c]quinoline-5N-oxideof Formula XXVI using a conventional oxidizing agent capable of formingN-oxides. The reaction is conveniently carried out by adding3-chloroperoxybenzoic acid to a solution of a compound of Formula XXV ina solvent such as dichloromethane or chloroform. The reaction can becarried out at ambient temperature, and the product can be isolatedusing conventional methods.

In step (6) of Reaction Scheme III, a pyrazolo[3,4-c]quinoline-5N-oxideof Formula XXVI is aminated to provide a pyrazolo[3,4-c]quinolin4-amineof Formula XVIIa, a subgenus of Formulas I, II, III, and Ia. Step (6)can be carried out by the activation of an N-oxide of Formula XXVI byconversion to an ester and then reacting the ester with an aminatingagent. Suitable activating agents include alkyl- or arylsulfonylchlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, orp-toluenesulfonyl chloride. Suitable aminating agents include ammonia,in the form of ammonium hydroxide, for example, and ammonium salts suchas ammonium carbonate, ammonium bicarbonate, and ammonium phosphate. Thereaction is conveniently carried out by adding ammonium hydroxide to asolution of the N-oxide of Formula XXVI in a suitable solvent such asdichloromethane or chloroform and then adding p-toluenesulfonylchloride. The reaction can be carried out at ambient temperature. Theproduct or pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

Alternatively step (6) can be carried out by the reaction of apyrazolo[3,4-c]quinoline-5N-oxide of Formula XXVI with trichloroacetylisocyanate followed by base-promoted hydrolysis of the resultingintermediate to provide a pyrazolo[3,4-c]quinolin-4-amine of FormulaXVIIa. The reaction is conveniently carried out in two steps by (i)adding trichloroacetyl isocyanate to a solution of the N-oxide ofFormula XXVI in a solvent such as dichloromethane and stirring atambient temperature to provide an isolable amide intermediate. In step(ii), a solution of the intermediate in methanol is treated with a basesuch as sodium methoxide at ambient temperature. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Pyrazolo[3,4-c]naphthyridines of the invention can be prepared accordingto Reaction Scheme IV, where R_(a), R_(1a), R_(2a), and n are as definedabove. In step (1) of Reaction Scheme IV, a bromo-substituted pyrazoleof Formula XXIV undergoes a transition-metal catalyzed cross couplingreaction with a reagent of Formula XVIII, where M is defined as above,or one of its isomers. Step (1) of Reaction Scheme IV can be carried outas described for step (5) of Reaction Scheme I, and under these reactionconditions an intramolecular addition can take place to provide thepyrazolo[3,4-c]naphthyridine of Formula XXVII.

In step (2) of Reaction Scheme IV, a pyrazolo[3,4-c]naphthyridine ofFormula XXVII is oxidized to a pyrazolo[3,4-c]naphthyridine-5N-oxide ofFormula XXVIII, which is aminated in step (3) to provide apyrazolo[3,4-c]naphthyridin-4-amine of Formula XXa, a subgenus ofFormulas I, II, VI, and Ia, or an isomer thereof. Steps (2) and (3) ofReaction Scheme IV can be carried out as described for steps (5) and(6), respectively, of Reaction Scheme III.

Tetrahydroquinolines of the invention may be prepared according toReaction Scheme V, where n is as defined above and R_(b), R_(1b), andR_(2b) are subsets of R, R₁, and R₂ as defined above that do not includethose substituents that one skilled in the art would recognize as beingsusceptible to reduction under the acidic hydrogenation conditions ofthe reaction. These susceptible groups include, for example, alkenyl,alkynyl, and aryl groups and groups bearing nitro substituents. However,a compound of Formula XVII bearing an aryl substituent at R₁, forexample, may be used as a substrate in the reaction to provide acompound of Formula XXIX where the aryl group is reduced. In thismanner, a phenylethyl group at R₁ may be converted to a cyclohexylethylgroup.

As shown in Reaction Scheme V, a pyrazolo[3,4-c]quinolin-4-amine ofFormula XVIIb can be reduced to a6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine of Formula XXIX, asubgenus of Formulas I, II, VIII, and Ia. The reaction may be carriedout under heterogeneous hydrogenation conditions by adding platinum (IV)oxide to a solution or suspension of the compound of Formula XVIIb in asuitable solvent such as trifluoroacetic acid and placing the reactionunder hydrogen pressure. The product or pharmaceutically acceptable saltthereof can be isolated by conventional methods.

Pyrazolo[3,4-c]pyridines of the invention can be prepared according toReaction Scheme VI, where R₁, R₂, R_(A2), and R_(B2) are as definedabove. In step (1) of Reaction Scheme VI, a bromo-substituted pyrazolecarbonitrile of Formula XIV undergoes a Sonogashira coupling reactionwith (trimethylsilyl)acetylene to provide a pyrazole carbonitrile ofFormula XXX. The reaction can be carried out according to the literatureprocedure, Sonogashira, K.; Tohda, Y.; Hagihara, N., Tetrahedron Lett.,4467 (1975).

Alternatively, an iodo-substituted pyrazole carbonitrile of Formula XIVamay be used as a starting material for Reaction Scheme VI. A compound ofFormula XIVa is prepared from a pyrazole carbonitrile of Formula XIII,shown in Reaction Scheme I. The iodination is conveniently carried outby treating a pyrazole carbonitrile of Formula XIII with iodinemonochloride in a suitable solvent such as dichloromethane in thepresence of a base such as potassium carbonate. The reaction can becarried out at ambient temperature, and the product can be isolated byconventional methods.

In step (2) of Reaction Scheme VI, the trimethylsilyl group of thepyrazole of Formula XXX is removed to provide the pyrazole of FormulaXXXI. Potassium carbonate in methanol or tetrabutylammonium fluoride intetrahydrofuran can be used to carry out the transformation.

In step (3) of Reaction Scheme VI, the acetylene of the pyrazole ofFormula XXXI is alkylated using conventional synthetic methods, Jacobs,T. L. in Organic Reactions, 5, 1, (1949), to provide a pyrazole ofFormula XXXII. The reaction can be carried out by deprotonation of thecompound of Formula XXXI with a base and reaction of the resultingcarbanion with an electrophile of Formula R_(B2)-Halide, for example,iodomethane. Step (3) can be omitted when R_(B2) is hydrogen.

For some embodiments, steps (1) through (3) of Reaction Scheme VI may bereplaced with one step from a compound of Formula XIVa using aSonogashira coupling reaction. The coupling is conveniently carried outby combining an alkyne of Formula R_(B2)—C═C—H, copper(I) iodide,dichlorobis(triphenylphosphine)palladium(II), and triethylamine in asuitable solvent such as acetonitrile and then heating at an elevatedtemperature, such as the reflux temperature of the solvent. The productof Formula XXXII can be isolated using conventional methods.

In step (4) of Reaction Scheme VI, a pyrazole of Formula XXXII reactswith ammonia to provide a pyrazolo[3,4-c]pyridin-4-amine of FormulaXIII, a subgenus of Formulas I, II, IX, and Ia. The reaction can becarried out by adding a solution of ammonia in methanol to the pyrazoleof Formula XXXII and heating at an elevated temperature, such as 150° C.The reaction may be carried out in a pressure vessel. The product orpharmaceutically acceptable salt thereof can be isolated by conventionalmethods.

Steps (5) and (6) may be carried out to provide a compound of Formula IXin which R_(A2) is other than hydrogen. In step (5) of Reaction SchemeVI, a pyrazolo[3,4-c]pyridin-4-amine of Formula XXXIII is brominatedunder conventional bromination conditions to provide a bromo-substitutedpyrazolo[3,4-c]pyridin-4-amine of Formula XXXIV, a subgenus of FormulasI, II, IX, and Ia. The reaction can be carried out as described in step(4) of Reaction Scheme I.

In step (6) of Reaction Scheme VI, a bromo-substitutedpyrazolo[3,4-c]pyridin4-amine of Formula XXXIV undergoes a transitionmetal catalyzed coupling reaction with a reagent of Formula R_(A2)-M,where R_(A2) is alkenyl, alkoxy, and —N(R₉)₂ to provide apyrazolo[3,4-c]pyridin-4-amine of Formula IX. Reagents of FormulaR_(A2)-M, where M is, for example, —B(OH)₂, —B(O-alkyl)₂, —Sn(alkyl)₃,and —Zn-Halide, are known to undergo coupling reactions. Thetransformation can be carried out by first protecting the amino group ofthe compound of Formula XXXIV, treating the protected compound with areagent of Formula R_(A2)-M in the presence of a transition metalcatalyst using conditions described in step (5) of Reaction Scheme I,and deprotecting the amine to provide the pyrazolo[3,4-c]pyridin4-amineof Formula IX. Alternatively, step (6) can be carried out by coupling acompound of Formula XXXIV with an alkyne under Sonogashira conditions asdescribed in step (1) of this reaction scheme. The resulting alkyne canbe reduced under conventional hydrogenation conditions to provide acompound of Formula IX, where R_(A2) is alkenyl or alkyl. Step (6) mayalso be carried out by (i) protecting the amino group of the compound ofFormula XXXIV, for example, with a Boc group; (ii) performing alithium-halogen exchange; (iii) treating with an electrophile of theFormula R_(A2)-Halide, for example iodomethane; and (iv) deprotectingthe amine to provide a compound of Formula IX. The product orpharmaceutically acceptable salt thereof can be isolated by conventionalmethods.

For some embodiments, compounds of the invention are prepared accordingto Reaction Scheme VII, wherein R, R₂, R₄, R₈, Q, M, and n are asdefined above. In step (1) of Reaction Scheme VII,4-phthalimido-2-butanone, which is obtained from the literatureprocedure, Eriks et al, J. Med. Chem., 35, 3239-3246, (1992), undergoesa Claisen condensation with diethyl oxalate under conventionalconditions to yield a compound of Formula XXXV.

In step (2) of Reaction Scheme VII, a compound of Formula XXXV reactswith a hydrazine of Formula R₂NHNH₂ to provide a pyrazole carboxylate ofFormula XXXVI. The reaction is conveniently carried out as described inStep (1) of Reaction Scheme I.

In steps (3) and (4) of Reaction Scheme VII, a pyrazole carboxylate ofFormula XXXVI is converted to a pyrazole carboxamide. In step (3) thepyrazole carboxylate of Formula XXXVI is first hydrolyzed under acidicconditions to provide a carboxylic acid of Formula XXXVII. The reactionis conveniently carried out by heating a mixture of the carboxylate ofFormula XXXVI in a mixture of hydrochloric acid and acetic acid at anelevated temperature, such as 100-120° C. The product can be isolated byconventional methods. In step (4), a carboxylic acid of Formula XXXVIIis then converted to its acid chloride. The reaction is convenientlycarried out by heating (115° C.) the carboxylic acid of Formula XXXVIIwith thionyl chloride in a suitable solvent such as toluene. The acidchloride can be isolated by conventional methods before converting it toa pyrazole carboxamide of Formula XXXVII. The conversion to the amide isconveniently carried out by adding concentrated ammonium hydroxide to asolution of the acid chloride in a suitable solvent such asdichloromethane. The reaction can be carried out at ambient temperature,and the product can be isolated using conventional methods.

In step (5) of Reaction Scheme VII, a pyrazole carboxamide of FormulaXXXVII is dehydrated to a pyrazole carbonitrile of Formula XXXIX.Suitable dehydrating agents include thionyl chloride, trifluoroaceticanhydride, and phosphorous oxychloride. The reaction is convenientlycarried out by treating a pyrazole carboxamide of Formula XXXVIII withexcess thionyl chloride in a suitable solvent such as toluene. Thereaction can be run at elevated temperture, for example, at the refluxtemperature of the solvent, and the product can be isolated usingconventional methods.

In step (6) of Reaction Scheme VII, a pyrazole carbonitrile of FormulaXXXIX is brominated according to the method described in step (4) ofReaction Scheme I to provide a bromo-substituted pyrazole carbonitrileof Formula XL.

In step (7) of Reaction Scheme VII, the phthalimide protecting group ofthe pyrazole of Formula XL is removed to reveal an amine, which is thenprotected by a tert-butoxycarbonyl (Boc) group. The deprotection isconveniently carried out by treating the compound of Formula XL withhydrazine in a suitable solvent such as ethanol. The reaction can be runat an elevated temperature, such as the reflux temperature of thesolvent, and the amine can be isolated using conventional methods. TheBoc protection is then conveniently carried out by treating the aminewith di-tert-butyl dicarbonate in a suitable solvent such as1-methyl-2-pyrrolidinone (NMP). The reaction can be carried out atambient temperature, and the product of Formula XLI can be isolated byconventional methods.

In steps (8) and (9a) of Reaction Scheme VII, a bromo-substitutedpyrazole carbonitrile of Formula XLI undergoes a transition-metalcatalyzed cross coupling reaction with a reagent of Formula XV to form apyrazole-substituted aniline of Formula XLIII, which undergoesintramolecular cyclization and removal of the Boc group under acidicconditions in step (9a) to provide a pyrazolo[3,4-c]quinoline of FormulaXLV, a subgenus of Formulas I, II, III, and Ia. Steps (8) and (9a) ofReaction Scheme VII can be carried out as described in steps (5) and (6)of Reaction Scheme I.

Alternatively, in step (8) of Reaction Scheme VII, a bromo-substitutedpyrazole carbonitrile of Formula XLI undergoes a Suzuki coupling with areagent of Formula XLII.

The resulting pivaloylamino-substituted compound undergoes abase-promoted intramolecular cyclization in step (9) of Reaction SchemeVII and subsequent cleavage of the pivaloyl group to provide apyrazolo[3,4-c]quinoline of Formula XLIV, a subgenus of Formulas I, II,III, and Ia. The reaction with XLII and the base-promoted cyclizationare carried out as described in steps (5) and (6) of Reaction Scheme I.The product or pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

In step (10) of Reaction Scheme VII, the Boc protecting group on apyrazolo[3,4-c]quinoline of Formula XLIV is removed to provide anaminoethyl pyrazolo[3,4-c]quinoline of Formula XLV, a subgenus ofFormulas I, II, III, and Ia. The deprotection is conveniently carriedout under acidic conditions by adding hydrogen chloride in ethanol to apyrazolo[3,4-c]quinoline of Formula XLIV in a suitable solvent such asethanol. The reaction can be run at ambient temperature, and the productor pharmaceutically acceptable salt thereof can be isolated usingconventional methods.

In step (11) of Reaction Scheme VII, anaminoethyl-2H-pyrazolo[3,4-c]quinoline of Formula XLV orpharmaceutically acceptable salt thereof is converted to an amide,sulfonamide, sulfamide, or urea of Formula XLVI using conventionalmethods. Formula XLVI represents a subgenus of Formula I, II, III, andIa. In step (11), an aminoethyl-2H-pyrazolo[3,4-c]quinoline of FormulaXLV can react with an acid chloride of Formula R₄C(O)Cl to provide acompound of Formula XLVI in which -Q- is —C(O)—. In addition, anaminoethyl-2H-pyrazolo[3,4-c]quinoline of Formula XLV can react withsulfonyl chloride of Formula R₄S(O)₂Cl or a sulfonic anhydride ofFormula (R₄S(O)₂)₂O to provide a compound of Formula XLVI in which -Q-is —S(O)₂—. Numerous acid chlorides of Formula R₄C(O)Cl, sulfonylchlorides of Formula R₄S(O)₂Cl, and sulfonic anhydrides of Formula(R₄S(O)₂)₂O are commercially available; others can be readily preparedusing known synthetic methods. The reaction is conveniently carried outby adding the acid chloride of Formula R₄C(O)Cl, sulfonyl chloride ofFormula R₄S(O)₂Cl, or sulfonic anhydride of Formula (R₄S(O)₂)₂O to asolution of the aminoethyl-2H-pyrazolo[3,4-c]quinoline of Formula XLV ina suitable solvent such as chloroform, dichloromethane, or DMF.Optionally a base such as triethylamine or N,N-diisopropylethylamine canbe added. The reaction can be carried out at ambient temperature or asub-ambient temperature such as 0° C. The product or pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

Ureas of Formula XLVI, where -Q- is —C(O)—N(R₈)— and R₈ is as definedabove, can be prepared by reacting anaminoethyl-2H-pyrazolo[3,4-c]quinoline of Formula XLV orpharmaceutically acceptable salt thereof with isocyanates of FormulaR₄N═C═O or with carbamoyl chlorides of Formula R₄N—(R₈)—C(O)Cl. Numerousisocyanates of Formula R₄N═C═O and carbamoyl chlorides of FormulaR₄N—(R₈)—C(O)Cl are commercially available; others can be readilyprepared using known synthetic methods. The reaction can be convenientlycarried out by adding the isocyanate of Formula R₄N═C═O or carbamoylchloride of Formula R₄N—(R₈)—C(O)Cl to a solution of theaminoethyl-2H-pyrazolo[3,4-c]quinoline of Formula XLV in a suitablesolvent such as DMF or chloroform. Optionally a base such astriethylamine or N,N-diisopropylethylamine can be added. The reactioncan be carried out at ambient temperature or a sub-ambient temperaturesuch as 0° C. Alternatively, a compound of Formula XLV can be treatedwith an isocyanate of Formula R₄(CO)N═C═O, a thioisocyanate of FormulaR₄N═C═S, or a sulfonyl isocyanate of Formula R₄S(O)₂N═C═O to provide acompound of Formula XLVI, where -Q- is —C(O)—N(R₈)—(CO)—, —C(S)—N(R₈)—,or —C(O)—N(R₈)—S(O)₂—, respectively. The product or pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

Sulfamides of Formula XLVI, where -Q- is —S(O)₂—N(R₈)—, can be preparedby reacting a compound or salt of Formula XLV with sulfuryl chloride togenerate a sulfamoyl chloride in situ, and then reacting the sulfamoylchloride with an amine of formula HN(R₈)R₄. Alternatively, sulfamides ofFormula XLVI can be prepared by reacting a compound of Formula XLV witha sulfamoyl chloride of formula R₄(R₈)N—S(O)₂Cl. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods. Many amines of Formula HN(R₈)R₄ and some sulfamoylchlorides of formula R₄(R₈)N—S(O)₂Cl are commercially available; otherscan be prepared using known synthetic methods. The product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

For some embodiments, compounds of the invention are prepared accordingto Reaction Scheme VII; wherein R, R₂, R₄, R₈, Q, M, Y, and n are asdefined above; X_(a) is alkylene optionally interrupted with one or more—O— groups, wherein there are at least three atoms in the linking chain;and R_(4a) is heterocyclyl that is unsubstituted or substituted asdefined in R₄ above, wherein the heterocyclyl is attached at a nitrogenatom. In step (1) of Reaction Scheme VIII, a chloro-substitutedketoester of Formula XLVII reacts with a hydrazine of Formula R₂NHNH₂ toprovide a pyrazole carboxylate of Formula XLVIII. Compounds of FormulaXLVII are readily prepared by reacting diethyl oxalate with ketones ofFormula CH3—C(O)-X_(a)-Cl under Claisen condensation conditions. Someketones of Formula CH₃C(O)—X_(a)—Cl are commercially available; otherscan be prepared by known synthetic methods. The reaction in step (1) isconveniently carried out as described in step (1) of Reaction Scheme I.

In step (2) of Reaction Scheme VIII, a chloro-substituted pyrazolecarboxylate of Formula XLVIII is converted to an acetate-substitutedpyrazole carboxylate of Formula XLIX. The reaction is convenientlycarried out by treating a chloro-substituted pyrazole carboxylate ofFormula XLVIII with potassium acetate and sodium iodide in a suitablesolvent such as DMF. The reaction can be carried out at an elevatedtemperature such as 90° C., and the product can be isolated usingconventional methods.

In step (3) of Reaction Scheme VIII, the ester group of a pyrazolecarboxylate of Formula XLIX is converted to an amide according to thereaction conditions described in step (2) of Reaction Scheme I. Underthe reaction conditions, the acetate group of the compound of FormulaXLIX is converted to a hydroxyl group to provide a compound of FormulaL, which can be isolated using conventional methods.

In step (4) of Reaction Scheme VIII, a pyrazole carboxamide of Formula Lis dehydrated to a pyrazole carbonitrile according to the reactionconditions described in step (3) of Reaction Scheme I. Under thesereaction conditions, the hydroxyl group of the compound of Formula L isconverted to a chloro group to provide a compound of Formula LI, whichcan be isolated using conventional methods.

In steps (5) and (6) of Reaction Scheme VIII, a pyrazole carbonitrile ofFormula LI is first brominated to provide a pyrazole carbonitrile ofFormula LII, which then undergoes a transition-metal catalyzed crosscoupling reaction to provide a pyrazole-substituted aniline of FormulaLIII. Steps (5) and (6) of Reaction Scheme VIII are conveniently carriedout as described in steps (4) and (5) of Reaction Scheme I.

In step (7) of Reaction Scheme VIII, the amine and nitrilefunctionalities of a pyrazole-substituted aniline of Formula LIII reactunder acidic conditions to form a pyrazolo[3,4-c]quinoline of FormulaLIV, which is a subgenus of Formulas I, I, III, and Ia. Theintramolecular addition is conveniently carried out by heating at refluxa pyrazole-substituted aniline of Formula LIII in the presence ofhydrogen chloride in a suitable solvent such as ethanol. The reactionmay also be carried out as described in step (6) of Reaction Scheme I.The product or pharmaceutically acceptable salt thereof can be isolatedby conventional methods.

In step (8) or (8a) of Reaction Scheme VIII, a chloro-substitutedpyrazolo[3,4-c]quinoline of Formula LIV reacts with a nucleophile toprovide a pyrazolo[3,4-c]quinoline of Formula LV or LVa, subgenera ofFormulas I, II, III, and Ia. For example, a compound of Formula LIV canreact with methanesulfonamide to provide a compound of Formula LV,wherein —Y—R₄ is —NH—S(O)₂—CH₃. The reaction is conveniently carried outby combining sodium hydride and methanesulfonamide in a suitable solventsuch as DMF and then adding a compound of Formula LIV and sodium iodide.The reaction can be carried out at an elevated temperature such as80-90° C. The product or pharmaceutically acceptable salt thereof can beisolated by conventional methods.

Also, in step (8) of Reaction Scheme VIII, the chloro group on apyrazolo[3,4-c]quinoline of Formula LIV can be displaced by a thiolunder basic conditions to provide a compound of Formula LV where —Y— is—S—. The reaction is conveniently carried out by adding a thiol to asolution of a pyrazolo[3,4-c]quinoline of Formula LIV in the presence ofa base such as potassium tert-butoxide in a suitable solvent such asDMF. The product or pharmaceutically acceptable salt thereof can beisolated by conventional methods. A compound of Formula LV where —Y— is—S— can then be oxidized to a compound of Formula LV where —Y— is—S(O)₂— using conventional oxidizing agents. The reaction isconveniently carried out by adding peracetic acid to the compound ofFormula LV where —Y— is —S— in a suitable solvent. The conversion of acompound of Formula LIV to a compound of Formula LV where —Y— is —S(O)₂—can conveniently be carried out in one pot without isolating thethioether from the reaction mixture. The product or pharmaceuticallyacceptable salt thereof can be isolated by conventional methods.

Alternatively, the chloro group of a pyrazolo[3,4-c]quinoline of FormulaLIV can displaced with potassium thioacetate. The reaction isconveniently carried out at ambient temperature by adding potassiumthioacetate to a solution of a pyrazolo[3,4-c]quinoline of Formula LIVin a suitable solvent such as DMF. The thioacetate group can then becleaved under basic conditions at ambient temperature by adding asolution of sodium methoxide in methanol to provide a compound ofFormula LV wherein —Y—R₄ is —SH. A thiol-substitutedpyrazolo[3,4-c]quinoline of Formula LV can then be oxidized by treatmentwith chlorine, prepared in situ from benzyltributylammonium chloride andtrichloroisocyanuric acid, in a suitable solvent such as dichloromethaneat 0° C. to provide a sulfonyl chloride, which is then treated with anamine hydrochloride of Formula (R₄)(R₈)NH.HCl followed by aqueouspotassium carbonate in a suitable solvent such as dichloromethane toprovide a compound of Formula LV wherein —Y— is —S(O)₂—N(R₈)—. Thereaction with the amine hydrochloride can be carried out at ambienttemperature, and the product can be isolated using conventional methods.

The chloro group on a pyrazolo[3,4-c]quinoline of Formula LIV can alsobe displaced by an amine of Formula

several of which are commercially available. Other amines of thisformula can be prepared by conventional methods. The reaction isconveniently carried out by combining a pyrazolo[3,4-c]quinoline ofFormula LIV and the amine in the presence of a base such as potassiumcarbonate and in a suitable solvent such as DMF. Catalytic sodium iodidecan optionally be added. The reaction can be carried out at an elevatedtemperature such as 50° C. or 90-100° C., and the product can beisolated by conventional methods. These reaction conditions can also beused employing a variety of tertiary amines to provide compounds ofFormula LV wherein Y is —N(R₈)—, a variety of phenols to providecompounds of Formula LV wherein Y is —O— and R₄ is an unsubstituted orsubstituted phenyl group, or employing a variety of commerciallyavailable cyclic amines in step (8a) to provide compounds of FormulaLVa.

In step (9) of Reaction Scheme VIII, the chloro group of apyrazolo[3,4-c]quinoline of Formula LIV is displaced by potassiumphthalimide to provide a pyrazolo[3,4-c]quinoline of Formula LVI. Thereaction is conveniently carried out by combining potassium phthalimide,sodium iodide, and a pyrazolo[3,4-c]quinoline of Formula LIV in asuitable solvent such as DMF and heating at an elevated temperature suchas 90-100° C. The product or pharmaceutically acceptable salt thereofcan be isolated by conventional methods.

In step (10) of Reaction Scheme VIII, the phthalimide protecting groupof the pyrazolo[3,4-c]quinoline of Formula LVI is removed to reveal anamine of Formula LVII, a subgenus of Formula I, II, III, and Ia. Thedeprotection is conveniently carried out by treating the compound ofFormula LVI with hydrazine in a suitable solvent such as ethanol. Thereaction can be run at an elevated temperature, such as the refluxtemperature of the solvent, and the product or pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

In step (11) of Reaction Scheme VIII, anaminoalkylpyrazolo[3,4-c]quinoline of Formula LVII or pharmaceuticallyacceptable salt thereof is converted to an amide, sulfonamide,sulfamide, or urea of Formula LVIII, which is a subgenus of Formulas I,II, III, and Ia. Step (11) of Reaction Scheme VIII can be carried outusing the procedures described for step (11) of Reaction Scheme VII. Theproduct or pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

Compounds of the invention are also prepared by Reaction Scheme IX,wherein R_(2c) is —R₄, —X_(c)—R₄, and —X_(c)—R₄; X_(c) is alkyleneoptionally terminated with arylene; and R, R₁, Y, R₄, and n are asdefined above. In step (1) of Reaction Scheme IX, the benzyl group of apyrazolo[3,4-c]quinoline of Formula LIX is cleaved to provide apyrazolo[3,4-c]quinoline of Formula LX, which is a subgenus of FormulasI, II, III, and Ia. Benzyl pyrazolo[3,4-c]quinolines of Formula LIX areavailable from the reactions shown in Reaction Schemes I, III, VII, andVIII using benzylhydrazine dihydrochloride in steps (1), (1), (2), and(1), respectively. Step (1) is conveniently carried out by heating thebenzyl pyrazolo[3,4-c]quinoline of Formula LIX in the presence ofhydrogen bromide and a suitable solvent such as acetic acid at anelevated temperature such as 150° C. Alternatively, the reaction can becarried out under hydrogenolysis conditions by exposing the benzylpyrazolo[3,4-c]quinoline of Formula LIX to hydrogen pressure in thepresence of a catalyst such as palladium on carbon in a suitable solventsuch as methanol. The reaction is conveniently carried out in a Parrvessel at ambient temperature or at an elevated temperature such as 50°C. The product of Formula LX or pharmaceutically acceptable salt thereofcan be isolated using conventional methods.

In addition to 2-benzyl pyrazolo[3,4-c]quinolines of Formula LIX,2-tert-butyl pyrazolo[3,4-c]quinolines are also convenient startingmaterials for Reaction Scheme IX. The cleavage of a tert-butyl group isconveniently carried out with aqueous hydrochloric acid at an elevatedtemperature, such as 100° C., and the product of Formula LX can beisolated by conventional methods.

In step (2) of Reaction Scheme IX, a pyrazolo[3,4-c]quinoline of FormulaLX is alkylated to provide a pyrazolo[3,4-c]quinoline of Formula LXI, asubgenus of Formulas I, II, III, and Ia. The reaction is convenientlycarried out by adding an alkyl halide of Formula Halide-R₄,Halide-X_(c)—R₄, or Halide-X_(c)—Y—R₄ to a pyrazolo[3,4-c]quinoline ofFormula LX in the presence of a base such as potassium carbonate in asuitable solvent such as DMF. The reaction can be run at ambienttemperature. Several alkyl halides of the Formulas Halide-R₄,Halide-X_(c)—R₄, and Halide-X_(c)—Y—R₄ are commercially available,including many substituted alkyl iodides and bromides and substitutedbenzyl iodides and bromides. Other alkyl halides can be prepared byknown synthetic methods. The product or pharmaceutically acceptable saltthereof can be isolated using conventional methods.

Various functional groups can be introduced in step (2) of ReactionScheme IX, and further synthetic elaboration is possible. For example,an alkyl halide of Formula Cl-alkylene-I can be used in step (2) toprovide a compound of Formula LXI, wherein R_(2c) is a chloroalkylenylgroup. The chloro group can then be displaced using one of a variety ofmethods described in steps (8) or (8a) of Reaction Scheme VIII. Inanother example, 4-bromobutylphthalimide can be used as the alkyl halidein step (2), and the resulting compound of Formula LXI bearing aphthalimide-protected amino group can be treated with hydrazinemonohydrate to remove the phthalimide group. The deprotection isconveniently carried out in a suitable solvent such as ethanol at anelevated temperature, such as the reflux temperature. The resultingaminoalkyl-substituted pyrazolo[3,4-c]quinoline of Formula LXI can thenbe treated according to step (11) of Reaction Scheme VII to provide acompound of Formula LXI wherein R₂, is -alkylene-N(R₈)-Q-R₄, and R₄, R₈,and Q are as defined above.

For some preferred embodiments, a compound of Formula LXI wherein R_(2c)is an ethoxy- or methoxyalkylenyl group is treated with boron tribromideto provide a compound of Formula LXI wherein R_(2c) is ahydroxyalkylenyl group. The reaction is conveniently carried out byadding a solution of boron tribromide to a compound of Formula LXI,wherein R_(2c) is an alkoxyalkylenyl group, in a suitable solvent suchas dichloromethane. The reaction can be run at a sub-ambient temperaturesuch as 0° C., and the product or pharmaceutically acceptable saltthereof can be isolated using conventional methods.

For some embodiments, tetrahydroquinolines of the invention can beprepared according to Reaction Scheme X, wherein R_(b), R_(2b), and nare as defined above and X_(b) is alkylene optionally interrupted orterminated by heterocyclylene and optionally interrupted by one or more—O— groups. Amino-substituted pyrazolo[3,4-c]quinolines of Formula LXIIor pharmaceutically acceptable salts thereof can be prepared using anyof the methods shown in Reaction Schemes I, VII, and VIII.

In step (1) of Reaction Scheme X, an amino-substitutedpyrazolo[3,4-c]quinoline of Formula LXII is reduced to atetrahydropyrazolo[3,4-c]quinoline of Formula LXIII according to themethod described in Reaction Scheme V. The product or pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

In step (2) of Reaction Scheme X, an amino-substitutedtetrahydropyrazolo[3,4-c]quinoline of Formula LXIII is converted to anamide, sulfonamide, sulfamide, or urea of Formula LXIV, which is asubgenus of Formulas I, II, VIII, and Ia. Step (2) of Reaction Scheme Xcan be carried out using the procedures described for step (11) ofReaction Scheme VII. The product or pharmaceutically acceptable saltthereof can be isolated using conventional methods.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme XI, wherein n is as defined above; R_(c) isR for pyrazolo[3,4-c]quinolines or R_(b) fortetrahydropyrazolo[3,4-c]quinolines; R_(2d) is R₂ forpyrazolo[3,4-c]quinolines or R_(2b) fortetrahydropyrazolo[3,4-c]quinolines; R₄, is R₄ as defined above, withthe proviso that the substituent on the alkyl, alkenyl, alkynyl,arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, orheterocyclyl group is not amino or alkylamino, or two R_(4s) groups inthe same molecule can join to form a saturated ring or partiallysaturated ring system optionally containing one or more heteroatoms;X_(d) is alkylene optionally interrupted by one or more —O— groups,wherein there are at least two atoms in the linking chain; Boc istert-butoxycarbonyl; and the bonds represented by dashed lines may bepresent or absent.

In step (1) of Reaction Scheme XI, the amino group of apyrazolo[3,4-c]quinoline or tetrahydropyrazolo[3,4-c]quinoline ofFormula LIVa is protected with two Boc groups to provide a compound ofFormula LXV. Pyrazolo[3,4-c]quinolines of Formula LIVa can be preparedaccording to steps (1) through (7) of Reaction Scheme VIII.Tetrahydropyrazolo[3,4-c]quinolines of Formula LIVa can be prepared byreducing a pyrazolo[3,4-c]quinoline of Formula LIVa according to themethod described in Reaction Scheme V. The protection reaction isconveniently carried out by combining a pyrazolo[3,4-c]quinoline or fortetrahydropyrazolo[3,4-c]quinoline of Formula LIVa with di-tert-butyldicarbonate in the presence of base, such as a combination oftriethylamine and catalytic 4-dimethylaminopyridine (DMAP). The reactioncan be carried out at ambient temperature in a suitable solvent such astoluene. The product can be isolated by conventional methods.

In step (2) of Reaction Scheme XI, a chloro-substituted compound ofFormula LXV is converted to an acetate-substitutedpyrazolo[3,4-c]quinoline or tetrahydropyrazolo[3,4-c]quinoline ofFormula LXVI according to the method described in step (2) of ReactionScheme VIII.

In step (3) of Reaction Scheme XI, the acetate protecting group of acompound of Formula LXVI is removed to provide a hydroxy-substitutedpyrazolo[3,4-c]quinoline or tetrahydropyrazolo[3,4-c]quinoline ofFormula LXVII. The reaction is conveniently carried out by combining acompound of Formula LXVI and potassium carbonate in a suitable solventsuch as methanol at ambient temperature. The product or pharmaceuticallyacceptable salt thereof can be isolated by conventional methods.

In step (4) of Reaction Scheme XI, the alcohol of Formula LXVII isoxidized to an aldehyde-substituted pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXVIII using conventionalmethods, for example, Swern oxidation conditions. The Swern oxidation isconveniently carried out by adding a compound of Formula LXVII followedby triethylamine to a mixture of oxalyl chloride and dimethylsulfoxidein a suitable solvent, such as dichloromethane. The reaction can becarried out at sub-ambient temperatures, such as −78° C., and theproduct can be isolated using conventional methods.

In step (5) of Reaction Scheme XI, an aldehyde-substituted compound ofFormula LXVIII is converted to an alkenyl- or alkynyl-substitutedcompound of Formula LXIX. The conversion to an alkynyl-substitutedcompound is conveniently carried out by adding diethyl1-diazo-2-oxopropylphosphonate to the aldehyde-substituted compound ofFormula LXVIII in the presence of a mild base such as potassiumcarbonate. The reaction is carried out in a suitable solvent such asdichloromethane or methanol at ambient temperature. Thealdehyde-substituted compound of Formula LXVIII can be converted to analkenyl-substituted compound of Formula LXIX using synthetic methodswell known to those skilled in the art; such methods include the Wittigreaction. The product can be isolated using conventional methods.

In step (6) of Reaction Scheme XI, the alkene or alkyne dipolarophile ofFormula LXIX undergoes a cycloaddition reaction with a nitrone ofFormula LXX or a nitrile oxide formed from an α-chloroaldoxime ofFormula LXXI to provide a isoxazole, isoxazoline, orisoxazolidine-substituted pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXXII. Nitrones of FormulaLXX are known and can be prepared by known methods. See, for example,Dicken, C. M. and DeShong, P., J. Org. Chem., 47, pp. 2047-2051 (1982).Nitrones of Formula LXX wherein two vicinal R_(4s) groups join to form asaturated carbon ring can be prepared according to the literatureprocedures: Thesing, J.; Sirrenberg, W., Chem. Ber., 92, p. 1748, (1959)and Iwashita, T. et al., J. Org. Chem., 47, p. 230, (1982). Thecycloaddition reaction shown in step (6) can be carried out by combiningthe nitrone of Formula LXX with a compound of Formula LXIX in a suitablesolvent such as toluene and heating at an elevated temperature, forexample, the reflux temperature of the solvent. Nitrones of Formula LXXcan also be prepared in situ by combining a hydroxylamine of FormulaR_(4s)—NH—OH or a hydrochloride salt thereof and an aldehyde or ketoneof Formula (R_(4s))₂C═O with a compound of Formula LXIX in the presenceof a base such as sodium bicarbonate and alumina. The reaction can becarried out at an elevated temperature in a suitable solvent such astoluene. The product can be isolated using conventional methods.

α-Chloroaldoximes of Formula LXXI can be prepared by treating analdoxime of Formula R_(4s)(H)C═N—OH with N-chlorosuccinimide at ambienttemperature or at a sub-ambient temperature such as 0° C. in a suitablesolvent such as DMF or THF. The resulting α-chloroaldoxime of FormulaLXXI is combined with a compound of Formula LXIX in the presence of abase such as triethylamine to generate a nitrile oxide in situ andeffect the cycloaddition reaction. The reaction can be carried out atambient temperature in a suitable solvent such as dichloromethane orTHF. The product can be isolated using conventional methods. When analkynyl-substituted compound of Formula LXIX is combined with anα-chloroaldoxime of Formula LXXI under these conditions, the product isan isoxazole of Formula LXXII.

In step (7) of Reaction Scheme XI, the Boc protecting groups are removedfrom a pyrazolo[3,4-c]quinoline or tetrahydropyrazolo[3,4-c]quinoline ofFormula LXXII according to the method described in step (10) of ReactionScheme VII. The reaction may be run at ambient temperature or at anelevated temperature such as 60° C., and the product of Formula LXXIIIor a pharmaceutically acceptable salt thereof can be isolated byconventional methods.

The Boc groups can be removed from other compounds shown in ReactionScheme XI to provide pyrazolo[3,4-c]quinolines ortetrahydropyrazolo[3,4-c]quinolines of the invention. For example, theconditions described in step (7) can be used to treat compounds ofFormula LXVII, LXVIII, or LXIX to revealpyrazolo[3,4-c]quinolin-4-amines ortetrahydropyrazolo[3,4-c]quinolin-4-amines with a hydroxy, aldehyde,alkene, or alkyne group at R₁.

Some compounds shown in Reaction Scheme XI are useful starting materialsfor the preparation of other compounds of the invention. For example, ahydroxyalkyl-substituted pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXVII can be treated withN-hydroxyphthalimide under Mitsunobu reaction conditions to provide anN-phthalimide-protected hydroxylamine. The reaction is convenientlycarried out by adding triphenylphosphine and N-hydroxyphthalimide to asolution of the alcohol of Formula LXVII in a suitable solvent such astetrahydrofuran or DMF and then slowly adding diisopropylazodicarboxylate. The reaction can be carried out at ambient temperatureor at an elevated temperature, such as 60° C. The phthalimide group canthen be removed from the resulting N-phthalimide-protected hydroxylamineby treatment with hydrazine at ambient temperature in a suitable solventsuch as ethanol. The resulting hydroxylamine can then be treated withone of numerous commercially available aldehydes or ketones in asuitable solvent such as methanol to provide an oxime. The Bocprotecting groups of the resulting compound can then be removed asdescribed in step (7) of Reaction Scheme XI to provide a compound of theinvention, wherein R₁ is —X—Y—R₄ or —X—R₅, where X is X_(d), which isdefined above, Y is —O—N═C(R₄)—, R₅ is

and R₄ a, b, and A′ are as defined above. Alternatively, thehydroxylamine prepared after the hydrazine deprotection may be treatedwith one of numerous acid chlorides, sulfonyl chlorides, isocyanates,carbamoyl chlorides, or sulfamoyl chlorides as described in step (11) ofReaction Scheme VII to provide, after removal of the Boc protectinggroups, a compound of the invention wherein R₁ is —X—Y—R₄ where X isX_(d), Y is —O—NH-Q-, and Q and R₄ are as defined above.

In another example, an aldehyde-substituted pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXVIII can optionally betreated with a Grignard reagent of Formula R₄—Mg—X under conventionalGrignard conditions to provide a secondary alcohol. It may be necessaryto remove the Boc groups prior to this reaction and install differentamine protecting groups known to one skilled in the art to be lessreactive toward Grignard reagents. The secondary alcohol can then beoxidized under Swern conditions as described in step (4) of ReactionScheme XI, and the protecting groups may subsequently be removed toprovide a ketone, which is a compound of the invention wherein R₁ is—X—Y—R₄ where X is X_(d), Y is —C(O)—, and R₄ is as defined above. Theketone can then be converted to an oxime by adding an aqueous solutionof a hydroxylamine salt of Formula NH₂OR₈.HCl to a solution of theketone in a suitable solvent such as methanol or ethanol and then addinga base such as sodium hydroxide and heating at an elevated temperatureto provide a compound of the invention, wherein R₁ is —X—Y—R₄ where X isX_(d)Y is —C(═N—OR₈)—, and R₄ and R₈ are as defined above. The oxime soprepared may be reduced with sodium cyanoborohydride in a mixture ofethanol or methanol in acetic acid to provide a hydroxylamine, which maybe treated with one of numerous acid chlorides, sulfonyl chlorides,isocyanates, carbamoyl chlorides, or sulfamoyl chlorides as described instep (11) of Reaction Scheme VII to provide a compound of the inventionwherein R₁ is —X—Y—R₄ where X is X_(d), Y is  CH(—N—(OR₈)-Q-R₄)-, and Q,R₄, and R₈ are as defined above.

Compounds of the invention can also be prepared according to ReactionScheme XII, wherein R_(c), R_(2d), Boc, R_(4s), X_(a), and n are asdefined above, and the bonds represented by dashed lines may be presentor absent. In steps (1) and (2) of Reaction Scheme XII, a1-chloroalkyl-substituted pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXVa, prepared accordingto the method described in step (1) of Reaction Scheme XI, is convertedto a 1-aminoalkyl-substituted compound of Formula LXXV. Step (1) isconveniently carried out by adding sodium azide and sodium iodide to a1-chloroalkyl-substituted compound of Formula LXVa in a suitable solventsuch as DMF. The reaction can be carried out at an elevated temperaturesuch as 90° C., and the azide of Formula LXXIV can be isolated byconventional methods prior to reduction in step (2). Step (2) isconveniently carried out by adding triphenylphosphine to anazide-substituted pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXXIV in a suitablesolvent or solvent mixture such as tetrahydrofuran/water. The reactioncan be carried out at ambient temperature, and the product can beisolated using conventional methods. Aminoalkyl-substitutedpyrazolo[3,4-c]quinolines or tetrahydropyrazolo[3,4-c]quinolines ofFormula LXXV may also be prepared using methods shown in Reaction SchemeVIII.

In step (3) of Reaction Scheme XII, an aminoalkyl-substitutedpyrazolo[3,4-c]quinoline or tetrahydropyrazolo[3,4-c]quinoline ofFormula LXXV is converted to an imine by reaction with a ketone oraldehyde of Formula (R_(4s))₂C═O and subsequently treated with anα-chloroaldoxime of Formula LXXI. The reaction is conveniently carriedout by combining an aminoalkyl-substituted compound of Formula LXXV witha ketone or aldehyde of Formula (R_(4s))₂C═O at ambient temperature in asuitable solvent such as dichloromethane. The reaction can optionally becarried out in the presence of magnesium sulfate. The resulting imine isthen combined with an α-chloroaldoxime of Formula LXXI according to theprocedure described in step (6) of Reaction Scheme XI. The product ofFormula LXXVI can be isolated using conventional methods.

In step (4) of Reaction Scheme XII, the Boc protecting groups areremoved from a pyrazolo[3,4-c]quinoline ortetrahydropyrazolo[3,4-c]quinoline of Formula LXXVI according to themethod described in step (7) of Reaction Scheme XI. The product ofFormula LXXVII or a pharmaceutically acceptable salt thereof can beisolated by conventional methods.

For some embodiments, compounds of the invention are prepared accordingto Reaction Scheme XIII, wherein R₁, R₂, and n are defined as above; Ris selected from the group consisting of halogen, alkyl, alkenyl,trifluoromethyl, and dialkylamino; and R_(3a) and R_(3b) are definedbelow. In step (1) of Reaction Scheme XIII, a bromo-substituted pyrazolecarbonitrile of Formula XIV undergoes a transition-metal catalyzed crosscoupling reaction with a reagent of Formula XLIIa. Some compounds ofFormula XLIIa are known; see, Adams, L., J. Heterocyclic Chem., 32, p.1171 (1995). Others can be prepared by known synthetic methods; see,Rocca, P. et al, Tetrahedron, 49, pp. 49-64 (1993). The Suzuki couplingreaction can be carried out as described in step (5) of Reaction SchemeI to provide a compound of Formula LXXVII, and the product can beisolated by conventional methods.

In step (2) of Reaction Scheme XIII, a pivaloylamino-substitutedcompound of Formula LXXVIII undergoes a base-promoted intramolecularcyclization and subsequent cleavage of the pivaloyl group to provide apyrazolo[3,4-c]quinoline of Formula XVIIa. The reaction can be carriedout as described in Reaction Scheme I, and the product orpharmaceutically acceptable salt thereof can be isolated by conventionalmethods.

In step (3) of Reaction Scheme XIII, the methoxy group of apyrazolo[3,4-c]quinoline of Formula XVIIa is demethylated to provide ahydroxy-substituted pyrazolo[3,4-c]quinoline of Formula XVIIb. Thedemethylation is conveniently carried out by treating the compound ofFormula XVIIa with a solution of boron tribromide in a suitable solventsuch as dichloromethane. The reaction can be carried out at asub-ambient temperature such as 0° C., and the product orpharmaceutically acceptable salt thereof can be isolated usingconventional methods. Alternatively, the demethylation is carried out byheating the compound of Formula XVIIa with anhydrous pyridinium chlorideat an elevated temperature, such as 210° C. The product orpharmaceutically acceptable salt thereof can be isolated by conventionalmethods.

In step (4) of Reaction Scheme XIII, the hydroxy group of apyrazolo[3,4-c]quinoline of Formula XVIIb is activated by conversion toa trifluromethanesulfonate (triflate) group. The reaction isconveniently carried out by treating a hydroxy-substitutedpyrazolo[3,4-c]quinoline of Formula XVIIb withN-phenyl-bis(trifluoromethanesulfonimide) in the presence of a tertiaryamine such as triethylamine. The reaction can be carried out at ambienttemperature in a suitable solvent such as DMF, and the triflate ofFormula LXXX can be isolated using conventional methods. The activationin step (4) may also be accomplished by converting the hydroxy group toanother good leaving group.

Step (5) of Reaction Scheme XIII can be carried out using knownpalladium-catalyzed coupling reactions such as the Suzuki coupling, Heckreaction, the Stille coupling, and the Sonogashira coupling. Forexample, a triflate-substituted pyrazolo[3,4-c]quinoline of Formula LXXXundergoes Suzuki coupling with a boronic acid of Formula R_(3a)—B(OH)₂,an anhydride thereof, or a boronic acid ester of FormulaR_(3a)—B(O-alkyl)₂; wherein R_(3a) is —R_(4b), —X_(e)—R₄, —X_(f)Y—R₄, or—X_(f)—R₅; where X_(e) is alkenylene; X_(f) is arylene, heteroarylene,and alkenylene interrupted or terminated by arylene or heteroarylene;R_(4b) is aryl or heteroaryl where the aryl or heteroaryl groups can beunsubstituted or substituted as defined in R₄ above; and R₄, R₅, and Yare as defined above. The coupling is carried out by combining acompound of Formula LXXX with a boronic acid or an ester or anhydridethereof in the presence of palladium (II) acetate, triphenylphosphine,and a base such as aqueous sodium carbonate in a suitable solvent suchas n-propanol. The reaction can be carried out at an elevatedtemperature, for example, at the reflux temperature. Numerous boronicacids of Formula R_(3a)—B(OH)₂, anhydrides thereof, and boronic acidesters of Formula R_(3a)—B(O-alkyl)₂ are commercially available; otherscan be readily prepared using known synthetic methods. The product ofFormula XVIIc or a pharmaceutically acceptable salt thereof can beisolated by conventional methods.

A compound of Formula XVIIc wherein R_(3a) is a heterocycle attachedthrough a nitrogen atom can be prepared in step (5) by reacting acompound of Formula LXXX with a nitrogen-containing heterocycle in thepresence of copper (I) iodide, potassium phosphate, and racemictrans-1,2-diaminocyclohexane in a suitable solvent such as 1,4-dioxane.The reaction can be carried out at an elevated temperature such as 110°C. In addition, this coupling can be carried out using apalladium-mediated coupling by combining a compound of Formula LXXX andthe nitrogen-containing heterocyclyl compound in the presence oftris(dibenzylideneacetone)dipalladium,(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, sodium tert-butoxide,and a suitable solvent such as toluene. The reaction can be carried outat an elevated temperature such as 80° C. The compound orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Alternatively, the Heck reaction can be used in step (5) of ReactionScheme XII to provide compounds of Formula XVIIc, wherein R_(3a) is—Xe—R_(4b) or —X_(e)—Y—R₄, wherein X_(e), Y, R₄, and R_(4b) are asdefined above. The Heck reaction is carried out by coupling a compoundof Formula LXXX with a compound of the Formula H₂C═C(H)—R_(4b) orH₂C═C(H)—Y—R₄. Several of these vinyl-substituted compounds arecommercially available; others can be prepared by known methods. Thereaction is conveniently carried out by combining the compound ofFormula LXXX and the vinyl-substituted compound in the presence ofpalladium (II) acetate, triphenylphosphine or tri-ortho-tolylphosphine,and a base such as triethylamine in a suitable solvent such asacetonitrile or toluene. The reaction can be carried out at an elevatedtemperature such as 100-120° C. under an inert atmosphere. The productof Formula XVIIc or pharmaceutically acceptable salt thereof can beisolated using conventional methods.

Compounds of Formula XVIIc, wherein R_(3a) is —X_(g)—R₄, X_(g) isalkynylene, and R₄ is as defined above, can also be prepared bypalladium catalyzed coupling reactions such as the Stille coupling orSonogashira coupling. These reactions are carried out by coupling acompound of Formula LXXX with a compound of the Formula(alkyl)₃Sn—C≡C—R₄, (alkyl)₃Si—C≡C—R₄, or H—C—C—R₄.

Compounds of Formula XVIIc prepared as described above bypalladium-mediated coupling reactions, wherein R_(3a) is —X_(e)—R₄,—X_(e)—Y—R₄, —X_(f2)—Y—R₄, —X_(f2)—R₅, or —X_(g)—R₄, where X_(f2) isalkenylene interrupted or terminated by arylene or heteroarylene, andX_(e), X_(g), Y, R₄, and R₅ are as defined above, can undergo reductionof the alkenylene or alkynylene group present to provide compounds ofFormula XVIIc wherein R_(3a) is —X_(h)—R₄, —X_(h)—Y—R₄, —X_(i)—Y—R₄, or—X_(i)—R₅, where X_(h) is alkylene; X_(i) is alkylene interrupted orterminated by arylene or heteroarylene; and R₄, R₅, and Y are as definedabove. The reduction can be carried out by hydrogenation using aconventional heterogeneous hydrogenation catalyst such as palladium oncarbon. The reaction can conveniently be carried out on a Parr apparatusin a suitable solvent such as ethanol, methanol, or mixtures thereof.The product or pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

In step (4a) of Reaction Scheme XIII, a hydroxy-substitutedpyrazolo[3,4-c]quinoline of Formula XVIIb is converted to a compound ofFormula XVIId, wherein R_(3b) is —O—R₄, —O—X—R₄, —O—X—Y—R₄, or —O—X—R₅,and X, Y, R₄, and R₅ are as defined above, using a Williamson-type ethersynthesis. The reaction is effected by treating a hydroxy-substitutedpyrazolo[3,4-c]quinoline of Formula XVIIb with an aryl, alkyl, orarylalkylenyl halide of Formula Halide-R₄, Halide-alkylene-R₄,Halide-alkylene-Y—R₄, or Halide-alkylene-R₅ in the presence of a base.Numerous alkyl, arylalkylenyl, and aryl halides of these formulas arecommercially available, including substituted benzyl bromides andchlorides, substituted or unsubstituted alkyl or arylalkylenyl bromidesand chlorides, bromo-substituted ketones, esters, and heterocycles, andsubstituted fluorobenzenes. Other halides of these formulas can beprepared using conventional synthetic methods. The reaction isconveniently carried out by combining an alkyl, arylalkylenyl, or arylhalide with the hydroxy-substituted compound of Formula XVIIb in asolvent such as DMF or N,N-dimethylacetamide in the presence of asuitable base such as cesium carbonate. Optionally, catalytictetrabutylammonium bromide can be added. The reaction can be carried outat ambient temperature or at an elevated temperature, for example 50° C.or 85° C., depending on the reactivity of the halide reagent.

Step (4a) of Reaction Scheme XIII can alternatively be carried out bytreating a compound of Formula XVIIb with an alcohol of FormulaHO-R_(3b) under Mitsunobu reaction conditions. Numerous alcohols offormulas HO-Z-Y—R₄, HO-Z-R₅, HO-Z-Het, and HO-Z-HetAr are commerciallyavailable; for example, 1-(3-hydroxypropyl)pyrrolidin-2-one,1-(2-hydroxyethyl)pyrrolidin-2-one, tert-butyl4-hydroxypiperidine-1-carboxylate, and 3-pyridylcarbinol. Other alcoholsof formula HO-R_(3b) can be prepared using conventional syntheticmethods. The reaction is conveniently carried out by out by addingtriphenylphosphine and an alcohol of Formula HO-R_(3b) to a solution ofa compound of Formula XVIIIb in a suitable solvent such astetrahydrofuran and then slowly adding diisopropyl azodicarboxylate ordiethyl azodicarboxylate. The reaction can be carried out at ambienttemperature or at a sub-ambient temperature, such as 0° C. The productcan be isolated using conventional methods.

Compounds prepared in step (4a) can undergo further syntheticelaboration. For example, in a compound of Formula XVIId wherein —R_(3b)is -Z-N(R₈)-Boc, prepared as described above, the Boc protecting groupcan be removed to provide an amino-substituted compound wherein —R_(3b)is -Z-N(R₈)H. A compound of Formula XVIId wherein —R_(3b) is —Z-N(R₈)Hcan be converted to a compound of Formula XVIId wherein —R_(3b) is-Z-N(R₈)-Q-R₄ using conventional methods such as the methods describedin step ( 11) of Reaction Scheme VII. A compound of Formula XVIIdwherein —R_(3b) is

prepared by methods described above, can be converted to a compound ofFormula XVIId wherein —R_(3b) is

using these same methods.

Alternatively, step (4a) may be carried out using the Ullmann ethersynthesis, in which an alkali metal aryloxide prepared from thehydroxy-substituted compound of Formula XVIIb reacts with an aryl halidein the presence of copper salts, to provide a compound of Formula XVIId,where R_(3b) is —O—R_(4b), —O—X_(j)—R₄, or —O—X_(j)—Y—R₄, wherein X_(j)is an arylene or heteroarylene and R_(4b) is as defined above. Numeroussubstituted and unsubstituted aryl halides are commercially available;others can be prepared using conventional methods. The product ofFormula XVIId, prepared by either of these methods, or pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme XIV, where R, R₁, R₂, R₃, n and m are asdefined above.

In step (1) of Reaction Scheme XIV, an indole of Formula LXXXI isacylated to provide an oxalated indole of Formula LXXXII. The reactioncan be carried out by adding ethyl chlorooxoacetate to a solution of anindole of Formula LXXXI in a suitable solvent such as diethyl ether inthe presence of pyridine. The reaction can be carried out at asub-ambient temperature such as 0° C. Many indoles of Formula LXXXI areknown. Some are commercially available and others can be readilyprepared using known synthetic methods.

In step (2) of Reaction Scheme XIV, an oxalated indole of Formula LXXXIIis rearranged to a pyrazolo[3,4-c]quinolin-4-one of Formula LXXXIII. Thereaction can be carried out by adding a hydrazine of Formula R₂NHNH₂ toa solution of an oxalated indole of Formula LXXXII in a solvent orsolvent mix such as ethanol/acetic acid in the presence of hydrochloricacid. The reaction can be carried out at an elevated temperature such asat reflux.

If step (2) is carried out using hydrazine, the resultingpyrazolo[3,4-c]quinolin-4-one of Formula LXXXII where R₂ is hydrogen canbe further elaborated using known synthetic methods. For example, apyrazolo[3,4-c]quinolin-4-one of Formula LXXXII where R₂ is hydrogen canbe alkylated, for example, as described in step (1) of Reaction SchemeI. Alternatively, a pyrazolo[3,4-c]quinolin-4-one of Formula LXXXIIIwhere R₂ is hydrogen can undergo a Buchwald amination with an arylhalide or heteroaryl halide. Numerous alkyl halides, aryl halides, andheteroaryl halides are commercially available; others can be preparedusing known synthetic methods.

Step (2) can also be carried out using a hydrazine that will install aremovable group at R₂. Examples of such hydrazines includebenzylhydrazine and tert-butylhydrazine. At a later point in thesynthetic pathway the group can be removed using conventional methods toprovide a compound in which R₂ is hydrogen. The compound may then befurther elaborated using the methods described above.

In step (3) of Reaction Scheme XIV, an aldehyde group is installed on apyrazolo[3,4-c]quinolin-4-one of Formula LXXXIII to provide apyrazolo[3,4-c]quinolin-4-one of Formula LXXXIV. The reaction can becarried out by deprotonating a pyrazolo[3,4-c]quinolin-4-one of FormulaLXXXIII with 2 equivalents of n-butyl lithium followed by treatment withDMF and quenching with hydrochloric acid. The reaction can be carriedout at an elevated temperature such as 50° C. in a suitable solvent suchas tetrahydrofuran.

In step (4) of Reaction Scheme XIV, a pyrazolo[3,4-c]quinolin-4-one ofFormula LXXXIV undergoes further elaboration using conventionalsynthetic methods to provide a pyrazolo[3,4-c]quinolin-4-one of FormulaLXXV. For example, the aldehyde can be reacted with several differentclasses of nucleophiles such as phosphonium ylides (Wittig olefination)or phosphonates (Homer Wadsworth olefination) to provide alkenes; aminesusing reductive amination to provide secondary or tertiary amines; andGrignard reagents or lithiated alkynes or alkenes to provide alcoholswhich may then be oxidized to provide ketones. When reaction with anucleophile provides a substituted olefin, the olefin may be reducedusing conventional methods such as hydrogenation using a conventionalheterogeneous hydrogenation catalyst such as palladium on carbon.Alternatively, the aldehyde can be reduced to the alcohol using knownmethods, for example, treating a solution of the aldehyde with sodiumborohydride. The alcohol can then be converted to a halide or an oxygenbased leaving group such as a triflate, mesylate, or tosylate usingconventional methods. The halide or oxygen based leaving group can thenbe reacted with a variety of nucleophiles.

In step (5) of Reaction Scheme XIV, a pyrazolo[3,4-c]quinolin-4-one ofFormula LXXXV is chlorinated to provide to provide a4-chloropyrazolo[3,4-c]quinoline of Formula LXXXVI. The reaction can becarried out by combining a pyrazolo[3,4-c]quinolin-4-one of FormulaLXXXV with phosphorous oxychloride and heating.

In step (6) of Reaction Scheme XIV, a 4-chloropyrazolo[3,4-c]quinolineof Formula LXXXVI is aminated to provide apyrazolo[3,4-c]quinolin-4-amine of Formula LXXXVII. The reaction can becarried out by treating a compound of Formula LXXXVI with ammonia in asuitable solvent such as ethanol at an elevated temperature, such as100° C. to 170° C. Pyrazolo[3,4-c]naphthyridines of the invention can beprepared by using an azaindole as the starting material in ReactionSchemes XIV. Azaindoles are known compounds. Some are commerciallyavailable and others can be prepared using known synthetic methods.Compounds of Formula LXXXVI wherein R₃ is a benzyloxy group are readilyprepared using the methods of Reaction Scheme XIV starting with acommercially available compound of Formula LXXXI. The benzyloxy groupcan be cleaved by hydrogenolysis, and the resulting hydroxy-substitutedcompound can be treated according to steps (4) and (5) or (4a) ofReaction Scheme XIII.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme XV, wherein R₁, R₂, R_(A1), R_(B1), Y″, andR₁₁ are as defined above. In Reaction Scheme XV, a pyrazole of FormulaII is converted to a compound of Formula II-1 using one of the methodsdescribed in step (11) of Reaction Scheme VII. For example, a compoundof Formula II can be treated with ethyl chloroformate or acetyl chloridein the presence of triethylamine in a suitable solvent such asdichloromethane. The reaction can be carried out at room temperature,and the product or pharmaceutically acceptable salt thereof can beisolated by conventional methods.

Some compounds of the invention may be transformed in vivo to othercompounds of the invention by mechanisms such as hydrolysis in theblood. For example, a compound wherein R₂ is —X—O—C(R₆)—R₄,—X—O—C(R₆)—O—R₄, or —X—O—C(R₆)—N(R₈)—R₄ would likely be transformed invivo to a compound wherein R₂ is —X—OH and therefore would be considereda prodrug of the hydroxy-substituted compound. Compounds of Formula II-1would be converted to compounds of Formula II.

Other prodrugs can be made from compounds of the invention. For example,a compound bearing a hydroxy substituent may be converted to an ester, acarbonate, a carbamate, or a sulfonate. Particularly useful esters aremade from carboxylic acids containing one to six carbon atoms ornaturally occurring L-amino acids. In addition, the amino group on the4-position of the imidazo ring compounds can be converted to an amide,amidine, or a carbamate to prepare a prodrug of a compound of theinvention. Particularly useful amides and carbamates contain one to fourcarbon atoms. The preparation of these prodrugs can be carried out bymethods well known to one of skill in the art.

Compounds of the invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis., USA) or are readily prepared usingmethods well known to those skilled in the art (e.g. prepared by methodsgenerally described in Louis F. Fieser and Mary Fieser, Reagents forOrganic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R.Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive OrganicFunctional Group Transformations, v 1-6, Pergamon Press, Oxford,England, (1995); Barry M. Trost and Ian Fleming, Comprehensive OrganicSynthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); orBeilsteins Handbuch der organischen Chemie, 4, Aufl. Ed.Springer-Verlag, Berlin, Germany, including supplements (also availablevia the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For more detailed description of theindividual reaction steps, see the EXAMPLES section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the compounds of the invention. Although specific startingmaterials and reagents are depicted in the reaction schemes anddiscussed below, other starting materials and reagents can be easilysubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the compounds prepared by the methodsdescribed below can be further modified in light of this disclosureusing conventional methods well known to those skilled in the art.

Conventional methods and techniques of separation and purification canbe used to isolate compounds of the invention, as well as variousintermediates related thereto. Such techniques may include, for example,all types of chromatography (high performance liquid chromatography(HPLC), column chromatography using common absorbents such as silicagel, and thin layer chromatography), recrystallization, and differential(i.e., liquid-liquid) extraction techniques.

Compounds of the invention can also be prepared using variations of thesynthetic routes shown in Reaction Schemes I through XIII that would beapparent to one of skill in the art. For example, the synthetic routesshown in Reaction Schemes VII or VIII for the preparation of quinolinescan be used to prepare naphthyridines by using a compound of FormulaXVIII or a position isomer thereof in lieu of a compound of Formula XV.Compounds of the invention can also be prepared using the syntheticroutes described in the EXAMPLES below.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound or salt of the invention as describedabove in combination with a pharmaceutically acceptable carrier.

The terms “a therapeutically effective amount” and “effective amount”mean an amount of the compound or salt sufficient to induce atherapeutic or prophylactic effect, such as cytokine induction,immunomodulation, antitumor activity, and/or antiviral activity.Although the exact amount of active compound or salt used in apharmaceutical composition of the invention will vary according tofactors known to those of skill in the art, such as the physical andchemical nature of the compound or salt, the nature of the carrier, andthe intended dosing regimen, it is anticipated that the compositions ofthe invention will contain sufficient active ingredient to provide adose of about 100 nanograms per kilogram (ng/kg) to about 50 milligramsper kilogram (mg/kg), preferably about 10 micrograms per kilogram(μg/kg) to about 5 mg/kg, of the compound or salt to the subject. Avariety of dosage forms may be used, such as tablets, lozenges,capsules, parenteral formulations, syrups, creams, ointments, aerosolformulations, transdermal patches, transmucosal patches and the like.

The compounds or salts of the invention can be administered as thesingle therapeutic agent in the treatment regimen, or the compounds orsalts of the invention may be administered in combination with oneanother or with other active agents, including additional immuneresponse modifiers, antivirals, antibiotics, antibodies, proteins,peptides, oligonucleotides, etc.

Compounds or salts of the invention have been shown to induce or inhibitthe production of certain cytokines in experiments performed accordingto the tests set forth below. These results indicate that the compoundsor salts are useful as immune response modifiers that can modulate theimmune response in a number of different ways, rendering them useful inthe treatment of a variety of disorders.

Cytokines whose production may be induced by the administration ofcompounds or salts of the invention generally include interferon-α(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds or salts of the invention include IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12, and a variety of other cytokines. Among other effects,these and other cytokines can inhibit virus production and tumor cellgrowth, making the compounds or salts useful in the treatment of viraldiseases and neoplastic diseases. Accordingly, the invention provides amethod of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound or salt or compositionof the invention to the animal. The animal to which the compound or saltor composition is administered for induction of cytokine biosynthesismay have a disease as described infra, for example a viral disease or aneoplastic disease, and administration of the compound or salt mayprovide therapeutic treatment. Alternatively, the compound or salt maybe administered to the animal prior to the animal acquiring the diseaseso that administration of the compound or salt may provide aprophylactic treatment.

In addition to the ability to induce the production of cytokines,compounds or salts of the invention can affect other aspects of theinnate immune response. For example, natural killer cell activity may bestimulated, an effect that may be due to cytokine induction. Thecompounds or salts may also activate macrophages, which in turnstimulate secretion of nitric oxide and the production of additionalcytokines. Further, the compounds or salts may cause proliferation anddifferentiation of B-lymphocytes.

Compounds or salts of the invention can also have an effect on theacquired immune response. For example, the production of the T helpertype 1 (T_(H)1) cytokine IFN-γ may be induced indirectly and theproduction of the T helper type 2 (T_(H)2) cytokines IL-4, IL-5 andIL-13 may be inhibited upon administration of the compounds or salts.

Other cytokines whose production may be inhibited by the administrationof compounds or salts of the invention include tumor necrosis factor-α(TNF-α). Among other effects, inhibition of TNF-α production can provideprophylaxis or therapeutic treatment of TNF-α mediated diseases inanimals, making the compounds or salt useful in the treatment of, forexample, autoimmune diseases. Accordingly, the invention provides amethod of inhibiting TNF-α biosynthesis in an animal comprisingadministering an effective amount of a compound or salt or compositionof the invention to the animal. The animal to which the compound or saltor composition is administered for inhibition of TNF-α biosynthesis mayhave a disease as described infra, for example an autoimmune disease,and administration of the compound or salt may provide therapeutictreatment. Alternatively, the compound or salt may be administered tothe animal prior to the animal acquiring the disease so thatadministration of the compound or salt may provide a prophylactictreatment.

Whether for prophylaxis or therapeutic treatment of a disease, andwhether for effecting innate or acquired immunity, the compound or saltor composition may be administered alone or in combination with one ormore active components as in, for example, a vaccine adjuvant. Whenadministered with other components, the compound or salt and othercomponent or components may be administered separately; together butindependently such as in a solution; or together and associated with oneanother such as (a) covalently linked or (b) non-covalently associated,e.g., in a colloidal suspension.

Conditions for which IRMs identified herein may be used as treatmentsinclude, but are not limited to:

-   -   (a) viral diseases such as, for example, diseases resulting from        infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II,        CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola        or vaccinia, or molluscum contagiosum), a picornavirus (e.g.,        rhinovirus or enterovirus), an orthomyxovirus (e.g.,        influenzavirus), a paramyxovirus (e.g., parainfluenzavirus,        mumps virus, measles virus, and respiratory syncytial virus        (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g.,        papillomaviruses, such as those that cause genital warts, common        warts, or plantar warts), a hepadnavirus (e.g., hepatitis B        virus), a flavivirus (e.g., hepatitis C virus or Dengue virus),        or a retrovirus (e.g., a lentivirus such as HIV);    -   (b) bacterial diseases such as, for example, diseases resulting        from infection by bacteria of, for example, the genus        Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella,        Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus,        Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus,        Neisseria, Clostridium, Bacillus, Corynebacterium,        Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia,        Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;    -   (c) other infectious diseases, such chlamydia, fungal diseases        including but not limited to candidiasis, aspergillosis,        histoplasmosis, cryptococcal meningitis, or parasitic diseases        including but not limited to malaria, pneumocystis carnii        pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and        trypanosome infection;    -   (d) neoplastic diseases, such as intraepithelial neoplasias,        cervical dysplasia, actinic keratosis, basal cell carcinoma,        squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma,        melanoma, leukemias including but not limited to myelogeous        leukemia, chronic lymphocytic leukemia, multiple myeloma,        non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell        lymphoma, and hairy cell leukemia, and other cancers;    -   (e) T_(H)2-mediated, atopic diseases, such as atopic dermatitis        or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and        Ommen's syndrome;    -   (f) certain autoimmune diseases such as systemic lupus        erythematosus, essential thrombocythaemia, multiple sclerosis,        discoid lupus, alopecia areata; and    -   (g) diseases associated with wound repair such as, for example,        inhibition of keloid formation and other types of scarring        (e.g., enhancing wound healing, including chronic wounds).

Additionally, an IRM compound or salt of the present invention may beuseful as a vaccine adjuvant for use in conjunction with any materialthat raises either humoral and/or cell mediated immune response, suchas, for example, live viral, bacterial, or parasitic immunogens;inactivated viral, tumor-derived, protozoal, organism-derived, fungal,or bacterial immunogens, toxoids, toxins; self-antigens;polysaccharides; proteins; glycoproteins; peptides; cellular vaccines;DNA vaccines; autologous vaccines; recombinant proteins; and the like,for use in connection with, for example, BCG, cholera, plague, typhoid,hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B,parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever,tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningococcaland pneumococcal vaccines, adenovirus, HIV, chicken pox,cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2,hog cholera, Japanese encephalitis, respiratory syncytial virus,rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.

Certain IRM compounds or salts of the present invention may beparticularly helpful in individuals having compromised immune function.For example, certain compounds or salts may be used for treating theopportunistic infections and tumors that occur after suppression of cellmediated immunity in, for example, transplant patients, cancer patientsand HIV patients.

Thus, one or more of the above diseases or types of diseases, forexample, a viral disease or a neoplastic disease may be treated in ananimal in need thereof (having the disease) by administering atherapeutically effective amount of a compound or salt of the inventionto the animal.

An amount of a compound or salt effective to induce or inhibit cytokinebiosynthesis is an amount sufficient to cause one or more cell types,such as monocytes, macrophages, dendritic cells and B-cells to producean amount of one or more cytokines such as, for example, IFN-α, TNF-α,IL-1, IL-6, IL-10 and IL-12 that is increased (induced) or decreased(inhibited) over a background level of such cytokines. The preciseamount will vary according to factors known in the art but is expectedto be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10μg/kg to about 5 mg/kg. The invention also provides a method of treatinga viral infection in an animal and a method of treating a neoplasticdisease in an animal comprising administering an effective amount of acompound or salt or composition of the invention to the animal. Anamount effective to treat or inhibit a viral infection is an amount thatwill cause a reduction in one or more of the manifestations of viralinfection, such as viral lesions, viral load, rate of virus production,and mortality as compared to untreated control animals. The preciseamount that is effective for such treatment will vary according tofactors known in the art but is expected to be a dose of about 100 ng/kgto about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amountof a compound or salt effective to treat a neoplastic condition is anamount that will cause a reduction in tumor size or in the number oftumor foci. Again, the precise amount will vary according to factorsknown in the art but is expected to be a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

In addition to the formulations and uses described specifically herein,other formulations, uses, and administration devices suitable forcompounds of the present invention are described in, for example,International Publication Nos. WO 03/077944 and WO 02/036592, U.S. Pat.No. 6,245,776, and U.S. publication Nos. 2003/0139364, 2003/185835,2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

EXAMPLES

Chromatographic purification was carried out by flash chromatography oneither a HORIZON HPFC system (an automated, modular high-performanceflash purification product available from Biotage, Inc, Charlottesville,Va., USA) or an Analogix INTELLIFLASH Flash Chromatography System (IFC).The eluent used for each purification is given in the example. In somechromatographic separations, the solvent mixture 80:18:2chloroform/methanol/concentrated ammonium hydroxide (CMA) was used asthe polar component of the eluent. In these separations, CMA was mixedwith chloroform in the indicated ratio. For Examples 1 through 6,chromatographic purification was carried out on a HORIZON HPFC systemusing either a FLASH 40+M cartridge, a FLASH 25+M, or a FLASH 65I Silicacartridge.

Examples 1-4

Part A

Ethyl 6-methyl-2,4-dioxoheptanoate, sodium salt is available from theliterature procedure (Claisen, L., Berichte, 1909, 42, 59) or can beprepared by the following method. A solution of diethyl oxalate (1equivalent) and 3-methyl-2-butanone (1 equivalent) was added dropwisewith vigorous stirring to a solution of sodium tert-butoxide (1equivalent) in ethanol. Following the addition, the reaction was stirredfor one hour; a precipitate formed. The precipitate was isolated byfiltration, washed with ethanol and diethyl ether, and dried to provideethyl 6-methyl-2,4-dioxoheptanoate, sodium salt.

Part B

Anhydrous hydrazine (3.58 g, 112 mmol) was added dropwise over a periodof 30 minutes to a solution of ethyl 6-methyl-2,4-dioxoheptanoate,sodium salt (24.8 g, 112 mmol) in acetic acid (160 mL). The reaction wasstirred overnight at ambient temperature, and then the solvent wasremoved under reduced pressure. The residue was dissolved in a mixtureof diethyl ether and water, and solid sodium bicarbonate and sodiumcarbonate were added to adjust the mixture to pH 8. The aqueous layerwas extracted twice with diethyl ether; the combined organic fractionswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on a HORIZON HPFC system (FLASH 65I cartridge, elutingwith 50:50 ethyl acetate/hexanes) to provide 21.0 g of ethyl5-(2-methylpropyl)-1H-pyrazole-3-carboxylate as a solid.

Part C

The alkylating agent from the table below (1.5 equivalents) and asolution of sodium ethoxide in ethanol (21%, 1.1 equivalents) were addedto a solution of ethyl 5-(2-methylpropyl)-1H-pyrazole-3-carboxylate (1equivalent) in ethanol (1M), and the reaction was heated at reflux undera nitrogen atmosphere for 90 minutes to two hours. An analysis byhigh-performance liquid chromatography (HPLC) indicated the presence ofstarting material. Additional sodium ethoxide solution (0.1-0.3equivalents) was added, and the reaction was heated at reflux for anadditional 30 minutes to two hours. For example 3, the reaction wasstirred at ambient temperature overnight instead of heating at reflux.The solvent was removed under reduced pressure, and the residue waspartitioned between aqueous sodium chloride and diethyl ether. Theaqueous layer was extracted twice with diethyl ether, and the combinedorganic fractions were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on a HORIZON HPFC system (FLASH 65I cartridge, elutingwith hexane/ethyl acetate ranging in ratios from 80:20 to 50:50) toprovide the alkylated pyrazole as a yellow oil.

Part D

Excess 30% ammonium hydroxide was added to a Parr vessel containing thematerial from Part C and methanol (1-2 M). The vessel was sealed, andthe reaction was heated at 100° C. for 12 hours, allowed to cool toambient temperature over a period of three hours, and then cooled to 0°C. A solid formed and was isolated by filtration, washed with water andhexanes, and air-dried to provide the carboxamides listed below.

Example 1:5-(2-Methylpropyl)-1-propyl-1H-pyrazole-3-carboxamide wasobtained as white crystals, mp 141-142.5° C.

Anal. Calcd. for C₁₁H₁₉N₃O: C, 63.13; H, 9.15; N, 20.08. Found: C,62.93; H, 8.89; N, 20.01.

Example 2: 1-Ethyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide wasobtained as white crystals, mp 125-126° C.

Anal. Calcd. for C₁₀H₁₇N₃O: C, 61.51; H, 8.78; N, 21.52. Found: C,61.50; H, 8.86; N, 21.58.

Example 3: At the completion of the reaction, the solvent was removedunder reduced pressure. The residue was purified by chromatography on aHORIZON HPFC system (FLASH 65I cartridge, eluting with ethylacetate/methanol ranging in ratios from 97:3 to 95:5) and subsequentlyrecrystallized from tert-butyl methyl ether to provide1-methyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide as white crystals,mp 118.5-119.5° C.

Anal. Calcd. for C₉H₁₅N₃O: C, 59.65; H, 8.34; N, 23.18. Found: C, 59.66;H, 8.66; N, 23.25.

Example 4: At the completion of the reaction, water was added toprecipitate the product,1-butyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide, which was isolatedas white crystals, mp 122.5-124° C.

Anal. Calcd. for C₁₂H₂₁N₃O: C, 64.54; H, 9.48; N, 18.82. Found: C,64.65; H, 9.52; N, 18.77.

Part E

A mixture of the carboxamide from Part D (5-10 g, 28-45 mmol) andphosphorous oxychloride (21-38 mL) was heated at 90° C. for 90 minutes.The solution was then poured into ice water (250-500 mL), andconcentrated ammonium hydroxide was added to adjust the mixture to pH7-8. The mixture was extracted with dichloromethane (4×), and thecombined extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide an oil.

Part F

Potassium acetate (1.5 equivalents) and bromine (1.1 equivalents) wereadded to a solution of the carbonitrile from Part E in acetic acid (0.6M), and the reaction was stirred for 15-24 hours. Saturated aqueoussodium hydrogensulfite (1 mL) was added, and the mixture was stirreduntil it became colorless. The acetic acid was removed under reducedpressure, and 2M aqueous sodium carbonate was added to the residue. Theresulting solution was extracted with dichloromethane (4×). The combinedextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The resulting oil was purified by chromatographyon a HORIZON HPFC system (FLASH 65I cartridge, eluting with hexane/ethylacetate ranging in ratios from 98:2 to 65:35) to provide an oil. InExample 2, 4-bromo-1-ethyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrilecrystallized under vacuum and was obtained as a white solid, mp 50-51°C.

Anal. Calcd. for C₁₀H₁₄N₃Br: C, 46.89; H, 5.51; N, 16.40. Found: C,46.95; H, 5.64; N, 16.75.

Part G

Triphenylphosphine (24 mg, 0.09 mmol) and palladium (II) acetate (7 mg,0.03 mmol) were added to a mixture of the carbonitrile from Part F (10.0mmol), 2-aminophenylboronic acid (12.0 mmol, Examples 2 and 3) or2-aminophenylboronic acid hydrochloride (12.0 mmol, Examples 1 and 4),aqueous sodium carbonate (6 mL of 2 M, Examples 2 and 3 or 12 mL of 2M,Examples 1 and 4), propanol (17.5 mL) and water (3.5 mL). The reactionwas heated under a nitrogen atmosphere at 100° C. for 12 to 33 hours; inExamples 3 and 4 additional triphenylphosphine, palladium (II) acetate,and boronic acid were added to drive the reaction to completion. Thereaction mixture was allowed to cool to ambient temperature and thenpartitioned between water and chloroform. The aqueous layer wasextracted with chloroform (3×). The combined organic fractions weredried over magnesium sulfate, filtered, and concentrated under reducedpressure.

The residue from Example 2 was purified by chromatography on a HORIZONHPFC system (40+M cartridge, eluting with dichloromethane/ethyl acetateranging in ratios from 100:0 to 85:15). The residue from Example 3 waspurified by chromatography on a HORIZON HPFC system (40+M cartridge,eluting with chloroform/CMA ranging in ratios from 99:1 to 95:5).

Part H

A solution of acetyl chloride (1.5 equivalents) in ethanol (0.3 M) wasstirred for 15 minutes and added to the material from Part G, and thereaction was heated at reflux under a nitrogen atmosphere for 3.5 to 14hours. The solvent was removed under reduced pressure, and the residuewas partitioned between chloroform and 2 M aqueous sodium carbonate. Theaqueous layer was extracted twice with chloroform, and the combinedorganic fractions were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on a HORIZON HPFC system (40+M cartridge, eluting withchloroform/CMA ranging in ratios from 100:0 to 75:25) and subsequentlyrecrystallized from acetonitrile. The crystals were dried overnight at6.65 Pa and 98° C. to provide the products listed below.

Example 1:1-(2-Methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine wasobtained as white needles, mp 199-200° C.

Anal. Calcd. for C₁₇H₂₂N₄: C, 72.31; H, 7.85; N, 19.84. Found: C, 72.13;H,8.03; N, 19.78.

Example 2: 2-Ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-aminewas obtained as white needles, mp 208-209° C.

Anal. Calcd. for C₁₆H₂₀N₄: C, 71.61; H. 7.51; N, 20.88. Found: C, 71.38;H. 7.83; N, 20.79.

Example 3:2-Methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine wasobtained as light pink crystals, mp 213-214° C.

Anal. Calcd. for C₁₅H₁₈N₄: C, 70.84; H, 7.13; N, 22.03. Found: C, 70.59;H, 7.19; N, 22.05.

Example 4: 2-Butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-aminewas obtained as white needles, mp 165-166° C.

Anal. Calcd. for C₁₈H₂₄N₄: C, 72.94; H, 8.16; N, 18.90. Found: C, 72.89;H, 7.99; N, 19.08. EXAMPLES 1-4

Example Alkylating agent in Part C R 1 1-Iodopropane —CH₂CH₂CH₃ 21-Bromoethane —CH₂CH₃ 3 Iodomethane —CH₃ 4 1-Iodobutane —CH₂CH₂CH₂CH₃

Example 5 1,2-Dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride

Part A

Ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate is available from theliterature procedure (Huppatz, J. L., Aust. J. Chem., 1983, 36,135-147). The general method described in Part D of Examples 1 through 4was used to convert ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate to1,5-dimethyl-1H-pyrazole-3-carboxamide.

Part B

The method described in Part E of Examples 1 through 4 was used to treat1,5-dimethyl-1H-pyrazole-3-carboxamide (5.0 g, 36 mmol) with phosphorousoxychloride (20 mL) to afford 3.9 g of1,5-dimethyl-1H-pyrazole-3-carbonitrile. A small portion wasrecrystallized from hexane to provide the following data.

Anal. Calcd. for C₆H₇N₃: C, 59.49; H, 5.82; N, 34.69. Found: C, 59.31;H, 5.75; N, 34.48.

Part C

A solution of bromine (5.1 g, 32 mmol) in acetic acid (10 mL) was addeddropwise to a solution of potassium acetate (3.9 g, 40 mmol) and1,5-dimethyl-1H-pyrazole-3-carbonitrile in acetic acid (50 mL).Following the addition, the reaction was stirred for 30 minutes.Saturated aqueous sodium hydrogensulfite was added, and the mixture wasstirred until it became colorless. The volatiles were removed underreduced pressure, and the residue was stirred with water to form asolid. The solid was isolated by filtration, washed with water, andrecrystallized from ethanol and then from hexane to provide 2.5 g of4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile as colorless needles, mp92-94° C.

Anal. Calcd. for C₆H₆BrN₃: C, 36.03; H, 3.02; N, 21.01. Found: C, 36.04;H, 2.86; N, 20.99.

Part D

Triphenylphosphine (2.4 mg, 0.09 mmol) and palladium (II) acetate (7 mg,0.03 mmol) were added to a mixture of4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (0.600 g, 3.00 mmol),2-aminophenylboronic acid (0.719 g, 5.25 mmol), aqueous sodium carbonate(1.8 mL of 2 M), propanol (5.25 mL) and water (1.1 mL). The reaction washeated under a nitrogen atmosphere at 100° C. for three hours and thenallowed to cool to ambient temperature. The work-up procedure describedin Part G of Examples 1-4 was followed. The resulting orange oil waspurified by chromatography on a HORIZON HPFC system (25+M cartridge,eluting with ethyl acetate/hexane ranging in ratios from 50:50 to 75:25)to provide 371 mg of4-(2-aminophenyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile as a paleyellow solid.

Part E

A solution of acetyl chloride (0.150 g, 1.9 mmol) in ethanol (6.4 mL)was stirred for 15 minutes.4-(2-Aminophenyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile (0.270 g, 1.27mmol) was added, and the reaction was heated at reflux under a nitrogenatmosphere for two hours. A precipitate formed. The mixture was allowedto cool to ambient temperature and then cooled to 0° C. The solid wasisolated by filtration, washed with diethyl ether, and dried to provide285 mg of 1,2-dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochlorideas a white solid, mp >250° C.

Anal. Calcd. for C₁₂H₁₂N₄-HCl: C, 57.95; H, 5.27; N, 22.53. Found: C,57.78; H, 5.23; N, 22.34.

Example 6N-[2-(4-Amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]benzamide

Part A

4-Methyl-4-benzamido-2-pentanone is available from the literatureprocedure (Scheuer, P. J. et al., J. Am. Chem. Soc., 1957, 22, 674-676)or from the following method. A mixture of mesityl oxide (19.6 g, 0.200mol) and benzonitrile (22.0 g, 0.210 mol) was cooled to 0° C.;concentrated sulfuric acid (20 mL) was added in 2 mL increments over aperiod of ten minutes. The reaction was heated to 35° C., and thereaction temperature rose quickly to 55° C. The reaction temperature wasmaintained at between 50 and 55° C. for one hour. The viscous liquid waspoured into ice water (800 mL), and the mixture was stirred for 90minutes. A solid formed and was isolated by filtration, washed withwater, washed with 2M aqueous sodium carbonate (100 mL), washed againwith water until the filtrate was pH neutral, and dried under nitrogenovernight. The solid was then recrystallized from tert-butyl methylether (150 mL) to provide 19.0 g of 4-methyl-4-benzamido-2-pentanone asbeige needles.

Part B

Sodium tert-butoxide (5.98 g, 62.2 mmol) was added to a solution of4-methyl-4-benzamido-2-pentanone (12.4 g, 56.5 mmol) and ethyldiethoxyacetate (11.0 g, 62.2 mmol) in ethanol (40 mL), and the reactionwas heated at reflux under a nitrogen atmosphere for 3.5 hours. Thesolvent was removed under reduced pressure, and the residue waspartitioned between saturated aqueous ammonium chloride and tert-butylmethyl ether. The aqueous solution was extracted twice with tert-butylmethyl ether, and the combined organic fractions were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toprovide 17.5 g of N-(6,6-diethoxy-1,1-dimethyl-3,5-dioxohexyl)benzamideas a brown oil.

Part C

Methyl hydrazine (2.60 g, 56.5 mmol) was added over a period of tenminutes to a solution of the material from Part B in ethanol (56 mL),and the reaction was stirred overnight at ambient temperature. Thesolvent was removed under reduced pressure, and the residue was purifiedby chromatography on a HORIZON HPFC system (FLASH 65I cartridge, elutingwith ethyl acetate/hexanes ranging in ratios from 50:50 to 90:10) toprovide 8.74 g ofN-[1-(5-diethoxymethyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamideas a viscous, yellow oil.

Part D

Hydrochloric acid (40 mL of 1 M) was added to a solution ofN-[1-(5-diethoxymethyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide(8.7 g, 24 mmol) in tetrahydrofuran (40 mL), and the reaction wasstirred for ten minutes. tert-Butyl methyl ether and 2 M aqueous sodiumcarbonate (20 mL) were added. The aqueous layer was extracted twice withtert-butyl methyl ether, and the combined organic fractions were driedover magnesium sulfate and filtered. Hexane was added, and the cloudymixture was stored overnight in the refrigerator. Crystals formed andwere isolated in two crops by filtration to provide 5.24 g ofN-[1-(5-formyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide asa white powder, mp 150-151° C.

Anal. Calcd. for C₁₆H₁₉N₃O₂: C, 67.35; H, 6.71; N, 14.73. Found: C,67.22; H, 6.89; N, 14.73.

Part E

The method described in Part F of Examples 1-4 was used to brominateN-[1-(5-formyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide(4.87 g, 17.1 mmol). The crude product was recrystallized from 50:50hexane/ethyl acetate (140 mL), and the crystals were washed with hexaneand dried for two hours under nitrogen to provide 4.91 g ofN-[1-(4-bromo-5-formyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamideas white crystals, mp 150-151° C. Anal. Calcd. for C₁₆H₁₈N₃O₂Br: C,52.76; H, 4.98; N, 11.54. Found: C, 52.85; H, 5.33; N, 11.54.

Part F

The method described in Part G of Examples 1-4 was used to coupleN-[1-(4-bromo-5-formyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide(3.64 g, 10.0 mmol) and 2-aminophenylboronic acid hydrochloride (2.08 g,12.0 mmol). The reaction was heated for 4 hours. The product waspurified by chromatography on a HORIZON HPFC system (40+M cartridge,eluting sequentially with ethyl acetate and 99:1 ethyl acetate/methanol)to provide 1.81 g ofN-[1,1-dimethyl-2-(2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]benzamideas an orange solid.

Part G

3-Chloroperoxybenzoic acid (2.12 g, available as a 77% pure mixture)(mCPBA) was added to a solution ofN-[1,1-dimethyl-2-(2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]benzamide(2.28 g, 6.36 mmol) in chloroform (25 mL), and the reaction was stirredfor 45 minutes at ambient temperature. Brine and 2 M aqueous sodiumcarbonate were added, and the aqueous layer was separated and extractedwith chloroform (6×). The combined organic fractions were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.

Part H

Under a nitrogen atmosphere, trichloroacetyl isocyanate (7.63 mmol) wasadded to a solution of the material from Part G in anhydrousdichloromethane (30 mL), and the reaction was stirred for 90 minutes atambient temperature. The solvent was removed under reduced pressure. Theresidue was dissolved in methanol (15 mL), and a solution of sodiummethoxide (1.5 mL, 25% in methanol) was added. The reaction was stirredfor two hours, and then the solvent was removed under reduced pressure.The resulting oil was partitioned between dichloromethane and aqueoussodium chloride. The aqueous layer was extracted with dichloromethane(5×), and the combined organic layers were dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resulting yellowsolid was purified by chromatography on a HORIZON HPFC system (40+Mcartridge, eluting with chloroform/CMA ranging in ratios from 100:0 to70:30) and recrystallized twice from acetonitrile (23 mL/g and 14 mL/g).The crystals were dried overnight at 6.65 Pa and 98° C. to provide 687mg ofN-[2-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]benzamideas beige needles, mp 194-196° C.

Anal. Calcd. for C₂₂H₂₃N₅O: C, 70.76; H, 6.21; N, 18.75. Found: C,70.54; H, 6.09; N, 18.85.

Example 7 2-Butyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Butylhydrazine oxalate (25 g, 140 mmol) was added over a period of 15minutes to a solution of ethyl 2,4-dioxovalerate (22.2 g, 140 mmol) andtriethylamine (210 mmol) in ethanol (140 mL). The resulting solution wasstirred overnight at ambient temperature and concentrated under reducedpressure. Hexane was added, and an insoluble solid was removed byfiltration. The hexane was removed under reduced pressure; the residuewas purified by chromatography on a HORIZON HPFC system (65I cartridge,eluting with hexanes/ethyl acetate in a gradient from 80:20 to 45:55) toprovide 18.1 g of ethyl 1-butyl-5-methyl-1H-pyrazole-3-carboxylate as apale yellow oil.

Part B

A solution of ethyl 1-butyl-5-methyl-1H-pyrazole-3-carboxylate (18.1 g,86.1 mmol) in methanol (25 mL) was treated with ammonium hydroxide (25mL) according to a modification of the method described in Part D ofExamples 1-4. At the end of the reaction, the methanol was removed underreduced pressure, and the remaining solution was cooled in arefrigerator. A precipitate formed, was isolated by filtration, and waswashed with water. The solid (9 g) was recrystallized from hexane (300mL) and ethyl acetate (30 mL), isolated by filtration, washed withhexane, and air-dried to provide 6.95 g of1-butyl-5-methyl-1H-pyrazole-3-carboxamide as colorless plates, mp113.5-114.5° C.

Anal. Calcd for C₉H₁₅N₃O: C, 59.65; H, 8.34; N, 23.18. Found: C, 59.79;H, 8.21; N, 23.28.

Part C

A mixture of 1-butyl-5-methyl-1H-pyrazole-3-carboxamide (6.9 g, 38 mmol)and phosphorous oxychloride (34.0 mL) was heated at 90° C. under anitrogen atmosphere for two hours and then allowed to cool to ambienttemperature overnight. The reaction was poured into ice water (300 mL);concentrated ammonium hydroxide (115 mL) was added. The mixture wasextracted with chloroform (3×), and the combined extracts were driedover magnesium sulfate, filtered, and concentrated under reducedpressure to provide 6.58 g of1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as a pale yellow oil.

Part D

1-Butyl-5-methyl-1H-pyrazole-3-carbonitrile (6.58 g, 38 mmol) wastreated with potassium acetate (57.2 mmol) and bromine (41.9 mmol) inacetic acid (50 mL) according to a modification of the method describedin Part F of Examples 1-4. The reaction provided 9.3 g of4-bromo-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as a colorless oilthat crystallized upon standing. The crystals were used withoutpurification.

Part E

A modification of the method described in Part G of Examples 1-4 wasused to couple 4-bromo-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile (2.42g, 10.0 mmol) and 2-aminophenylboronic acid hydrochloride (2.43 g, 14.0mmol). Palladium (II) acetate was added as a 5 mg/mL solution in toluene(1.3 mL). The reaction was heated under nitrogen for 17 hours andcombined with the product mixture from another run before beingsubjected to the work-up procedure. The crude product was purified bychromatography on a HORIZON HPFC system (40+M cartridge, eluting withchloroform:CMA in a gradient from 100:0 to 80:20) to provide 3.17 g of4-(2-aminophenyl)-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as anorange oil. A small amount (0.21 g) of2-butyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine was also obtained asa beige powder.

Part F

Acetyl chloride (15 mmol) and ethanol (50 mL) were combined and added to4-(2-aminophenyl)-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile (3.17 g)according to the method described in Part H of Examples 1-4. Thereaction was heated for 16 hours. Following the work-up procedure,chromatographic purification, and recrystallization from acetonitrile(195 mL/g) 873 mg of 2-butyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminewere obtained as white needles, mp 220-222° C.

MS (APCI) m/z 255 (M+H)⁺;

Anal. Calcd for C₁₅H₁₈N₄: C, 70.84; H, 7.13; N, 22.03. Found: C, 70.64;H, 6.94; N, 22.14.

Example 8 2-Benzyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Potassium acetate (49.1 g, 0.500 mol) was added with stirring to asolution of ethyl 6-methyl-2,4-dioxoheptanoate, sodium salt (44.4 g,0.200 mol), prepared as described in Part A of Examples 1-4, in aceticacid (280 mL). The solution was cooled to 10° C., and benzylhydrazinedihydrochloride (39.0 g, 0.200 mol) was added in portions over a periodoften minutes while the reaction temperature was maintained between 10°C. and 13.5° C. The reaction was stirred for 90 minutes at between 6° C.and 13.6° C., allowed to warm to ambient temperature, stirred overnight,and concentrated under reduced pressure. The residue was partitionedbetween 2 M aqueous sodium carbonate (900 mL) and tert-butyl methylether (600 mL). The aqueous layer was extracted with tert-butyl methylether (2×300 mL), and the combined organic fractions were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toprovide 56.6 g of ethyl1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxylate as an oil orange.The product contained 10 mol % of ethyl2-benzyl-5-(2-methylpropyl)-2H-pyrazole-3-carboxylate.

Part B

A solution of ethyl1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxylate (30 g) in methanol(60 mL) was treated with ammonium hydroxide (60 mL) according to amodification of the method described in Part D of Examples 1-4. Thereaction was heated for 14 hours. At the end of the reaction, themethanol was removed under reduced pressure, and the remaining solutionwas extracted with tert-butyl methyl ether (3×). The combined extractswere dried over magnesium sulfate, filtered, and concentrated underreduced pressure. Toluene was added twice and removed under reducedpressure to remove residual water. Hexane was added to the residue;crystals formed and were isolated by filtration, washed with hexane, andair-dried overnight to provide 6.93 g of1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide as small,off-white crystals.

Part C

A mixture of 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide (6.77g, 26.3 mmol) and phosphorous oxychloride (19 mL) was heated at 90° C.under a nitrogen atmosphere for 90 minutes and then allowed to cool toambient temperature. The reaction was poured into ice water (250 mL);concentrated ammonium hydroxide (64 mL) was added. The mixture wasextracted with tert-butyl methyl ether (3×150 mL), and the combinedextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to provide 6.28 g of1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile as a pale orangeoil.

Part D

1-Benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (6.28 g, 26.2mmol) was treated with potassium acetate (3.9 g, 39 mmol) and bromine(4.61 g, 28.8 mmol) in acetic acid (52 mL) according to the methoddescribed in Part F of Examples 1-4. Following chromatographicpurification (eluting with hexanes/ethyl acetate in a gradient from 95:5to 70:30) 7.8 g of4-bromo-1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile wereobtained as a colorless oil containing 11 mol % of the startingmaterial.

Part E

The method described in Part G of Examples 1-4 was used to couple4-bromo-1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (3.18 g,10.0 mmol) and 2-aminophenylboronic acid hydrochloride (2.60 g, 15.0mmol) in the presence of palladium (II) acetate (22.5 mg),triphenylphosphine (79 mg), and 2 M aqueous sodium carbonate (15 mL).The product,4-2(-aminophenyl)-1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile,was used without purification.

Part F

The material from Part E was treated according to the method describedin Part H of Examples 1-4. Following the work-up procedure andchromatographic purification (eluting with chloroform/CMA in a gradientfrom 97:3 to 87:13), 1.81 g of product were obtained as a beige solid. Aportion (0.63 g) was recrystallized from acetonitrile (28.6 mL/g),isolated by filtration, washed with acetonitrile, and dried for 36 hoursin a vacuum oven at 65° C. to provide 559 mg of2-benzyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine as large,beige needles, mp 194-196° C.

MS (APCI) m/z 331 (M+H)⁺;

Anal. Calcd for C₂₁H₂₂N₄: C, 76.33; H, 6.71; N, 16.96. Found: C, 76.03;H, 6.84; N, 16.97.

Example 9 1-(2-Methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Hydrogen bromide (10 mL of 30% by weight in acetic acid) and2-benzyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.75 g,2.27 mmol) were combined in a TEFLON-lined Parr vessel and heated at150° C. for 24 hours and then allowed to cool to ambient temperatureover five hours. The reaction was filtered to remove a solid, and thefiltrate was adjusted to pH 7 with the addition of 50% sodium hydroxideand 2M aqueous sodium carbonate. A precipitate formed and was isolatedby filtration, washed with water, and air-dried. The solid was purifiedby chromatography on a HORIZON HPFC system (25+M cartridge, eluting withchloroform/CMA in a gradient from 80:20 to 40:60) followed byrecrystallization from acetonitrile (19 mL/g) and a small amount ofmethanol. The crystals were isolated by filtration, washed withacetonitrile, and dried for 36 hours in a vacuum oven at 65° C. toprovide 139 mg of 1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amineas small, pale orange needles, mp 248-249° C.

MS (APCI) m/z 241 (M+H)⁺;

Anal. Calcd for C₁₄H₁₆N₄.0.17 CH₃OH.0.16H₂O: C, 68.45; H, 6.89; N,22.53. Found: C, 68.43; H, 6.87; N, 22.53.

Example 10 1-Ethyl-2-methyl-2H-pyrazolo[3,4-clquinolin-4-amine

Part A

Sodium tert-butoxide (66.64 g, 0.693 mol) was added over a period of 20minutes to ethanol (450 mL) under a nitrogen atmosphere. When all solidshad dissolved, a mixture of diethyl oxalate (101.28 g, 0.693 mol) and2-butanone (50.0 g, 0.693 mol) was added over a period of 12 minutes.The reaction was stirred at ambient temperature for 1.5 hours and thenused in the next step.

Part B

The solution from Part A was treated with glacial acetic acid (115 mL)and then cooled to 0° C. Methylhydrazine (36.5 mL, 0.693 mmol) wasslowly added over a period of 20 minutes. The reaction was allowed towarm to ambient temperature, stirred for two hours, and concentratedunder reduced pressure. The residue was made basic with the addition of2 M aqueous sodium carbonate and extracted with tert-butyl methyl ether(3×400 mL). The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide 100 g of ared oil. Half of the oil was purified by chromatography on a HORIZONHPFC system (eluting with hexanes:ethyl acetate in a gradient from 100:0to 0:100 to provide 6.53 g of ethyl5-ethyl-1-methyl-1H-pyrazole-3-carboxylate as a yellow oil.

Part C

A mixture of ethyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (5.03 g,27.6 mmol) and ammonium hydroxide (28 mL of 30%) was stirred for 18hours at ambient temperature. A precipitate formed, was isolated byfiltration, and washed with cold hexanes to provide 2.60 g of5-ethyl-1-methyl-1H-pyrazole-3-carboxamide as a white solid, mp 170-172°C.

Anal. Calcd for C₇H₁₁N₃O: C, 54.89; H, 7.24; N, 27.43. Found: C, 54.87;H, 7.56; N, 27.58.

The product was mixed with material from another run.

Part D

5-Ethyl-1-methyl-1H-pyrazole-3-carboxamide (3.8 g, 25 mmol) was treatedwith phosphorous oxychloride (18 mL, 0.19 mol) according to the methoddescribed in Part C of Example 8 to provide 2.68 g of5-ethyl-1-methyl-1H-pyrazole-3-carbonitrile as a yellow oil.

Part E

5-Ethyl-1-methyl-1H-pyrazole-3-carbonitrile (2.68 g, 19.8 mmol) wastreated with potassium acetate (2.91 g, 29.7 mmol) and bromine (3.16 g,19.8 mmol) in acetic acid (25 mL) according to a modification of themethod described in Part F of Examples 1-4. The extraction was carriedout with tert-butyl methyl ether, and the combined extracts were driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide 3.8 g of a white solid. A small portion of the solid wasrecrystallized from ethanol to provide4-bromo-5-ethyl-1-methyl-1H-pyrazole-3-carbonitrile as long, whiteneedles, mp 72-74° C.

Anal. Calcd for C₇H₈BrN₃: C, 39.28; H, 3.77; N, 19.63. Found: C, 39.26;H, 3.55; N, 19.63.

Part F

A modification of the method described in Part G of Examples 1-4 wasused to couple 4-bromo-5-ethyl-1-methyl-1H-pyrazole-3-carbonitrile (1.65g, 7.7 mmol) and 2-aminophenylboronic acid hydrochloride (2.01 g, 11.6mmol) in the presence of palladium (II) acetate (17.3 mg, 0.077 mmol),triphenylphosphine (60.6 mg, 0.23 mmol), and 2 M aqueous sodiumcarbonate (11.6 mL). At the end of the reaction, tert-butyl methyl etherwas added. The aqueous phase was separated and extracted with tert-butylmethyl ether (2×); the combined organic fractions were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide amixture of 4-(2-aminophenyl)-5-ethyl-1-methyl-1H-pyrazole-3-carbonitrileand 1-ethyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part G

Ethanol (12 mL) was cooled to 0° C., and acetyl chloride (0.91 g, 12mmol) was added. The solution was allowed to warm to ambient temperatureand stirred for 30 minutes. A suspension of the material from Part F inethanol (5 mL) was added, and the mixture was heated at reflux for fourhours. The reaction was allowed to cool to ambient temperature. Aprecipitate was present, isolated by filtration, and combined withmaterial from another run. Chloroform (4 mL) and 2 M aqueous sodiumcarbonate were added, and the mixture was stirred for six hours. Aprecipitate formed and was isolated by filtration, washed sequentiallywith cold water and cold hexanes, and dried in a vacuum oven at 60° C.to provide 0.85 g of 1-ethyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 257-259° C.

Anal. Calcd for C₁₃H₁₄N₄.0.2 H₂O: C, 67.92; H, 6.31; N, 24.37. Found: C,67.69; H, 6.40; N, 24.76.

Example 11 1,2-Diethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A solution of ethyl 2,4-dioxohexanoate (0.345 mol), prepared asdescribed in Part A of Example 10, in glacial acetic acid (350 mL) wascooled to 0° C. Ethylhydrazine oxalate (41.43 g, 0.276 mol) was addedover a period of 20 minutes. The reaction was allowed to warm to ambienttemperature, stirred for 20 hours, and concentrated under reducedpressure. The residue was adjusted to pH 10 with the addition of 2 Maqueous sodium carbonate, and chloroform was added. The mixture wasfiltered to remove a solid. The aqueous filtrate was extracted withchloroform (3×), and the combined organic fractions were dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide 29.4 g of ethyl 1,5-diethyl-1H-pyrazole-3-carboxylate as anorange oil, which was used without purification.

Part B

A mixture of ethyl 1,5-diethyl-1H-pyrazole-3-carboxylate (29.4 g, 0.50mol) and ammonium hydroxide (150 mL of 30%) was stirred overnight atambient temperature. An analysis by thin layer chromatography (TLC)indicated the reaction was incomplete. The reaction was then heated for14 hours at 125° C. in a pressure vessel, allowed to cool to ambienttemperature, and cooled to 0° C. A precipitate formed, was isolated byfiltration, and washed with cold hexanes to provide 8.3 g of1,5-diethyl-1H-pyrazole-3-carboxamide as a white solid, mp 129-131° C.

Anal. Calcd for C₈H₁₃N₃O: C, 57.47; H, 7.84; N, 25.13. Found: C, 57.37;H, 8.04; N, 25.43.

Part C

1,5-Diethyl-1H-pyrazole-3-carboxamide (8.3 g, 0.050 mol) was treatedwith phosphorous oxychloride (35 mL) according to the method describedin Part C of Example 7. The reaction was heated for 2.5 hours to provide7.6 g of 1,5-diethyl-1H-pyrazole-3-carbonitrile as a yellow oil, whichwas used without purification.

Part D

The material from Part C was treated with potassium acetate (7.30 g,7.44 mmol) and bromine (7.92 g, 49.6 mmol) in acetic acid (60 mL)according to a modification of the method described in Part F ofExamples 1-4. The reaction was cooled in an ice bath during the additionof bromine. After the addition, the reaction was stirred at ambienttemperature over three days. The extraction was carried out withchloroform (3×100 mL), and the combined extracts were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide9.4 g of 4-bromo-1,5-diethyl-1H-pyrazole-3-carbonitrile as an orangeoil, which crystallized to an orange solid. The product was used withoutpurification.

Part E

4-Bromo-1,5-diethyl-1H-pyrazole-3-carbonitrile (4.56 g, 20.0 mmol) and2-aminophenylboronic acid hydrochloride (5.20 g, 30.0 mmol) were coupledin the presence of palladium (II) acetate (45 mg, 0.20 mmol),triphenylphosphine (157 mg, 0.599 mmol), and 2 M aqueous sodiumcarbonate (30 mL) according to the method described in Part F of Example10. The product,4-(2-aminophenyl)-1,5-diethyl-1H-pyrazole-3-carbonitrile, was usedwithout purification.

Part F

The material from Part E was added to a solution of acetyl chloride(2.36 g, 30.0 mmol) in ethanol (30 mL) according to a modification ofthe method described in Part G of Example 10. The reaction was heated atreflux for six hours and then heated at 81° C. overnight. The crudeproduct was purified by chromatography on a HORIZON HPFC system (elutingwith a gradient of chloroform/CMA) followed by recrystallization fromacetonitrile. The crystals were heated a second time in acetonitrile inthe presence of activated charcoal, which was removed by hot filtration,and recrystallized to provide 0.440 g of1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as an off-whitecrystalline solid, mp 234-236° C.

Anal. Calcd for C₁₄H₁₆N₄: C, 69.97; H, 6.71; N, 23.31. Found: C, 69.93;H, 7.03; N, 23.61.

Example 122-Ethyl-1-(2-methanesulfonylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Diethyl oxalate (19.8 g, 135 mmol) and 4-methylthio-2-butanone (16 g,135 mmol) were added to a solution of potassium tert-butoxide (13 g, 135mmol) in ethanol (97 mL) according to the method described in Part A ofExample 10.

Part B

Acetic acid (38 mL) and potassium acetate (20 g, 200 mmol) weresequentially added to the solution from Part A. The resulting suspensionwas cooled to 0° C., and ethylhydrazine oxalate (20.3 g, 135 mmol) wasadded with vigorous stirring over a period of ten minutes. The reactionwas stirred for 15 minutes at 0° C. and for one hour at ambienttemperature and then concentrated under reduced pressure. Saturatedaqueous sodium carbonate was added to adjust the residue to pH 9, andwater was added. The mixture was extracted with dichloromethane (2×100mL), and the combined extracts were washed with brine (100 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressure.The resulting dark oil was purified by column chromatography on silicagel (eluting with 1:1 ethyl acetate/hexanes) to provide 8.8 g of ethyl1-ethyl-5-(2-methylsulfanylethyl)-1H-pyrazole-3-carboxylate as an orangeoil.

Part C

mCPBA (17.9 g, 72.6 mmol, 70% pure) was added in portions to a solutionof ethyl 1-ethyl-5-(2-methylsulfanylethyl)-1H-pyrazole-3-carboxylate(8.8 g, 36 mmol) over a period of 15 minutes. The reaction was thenstirred at ambient temperature for 20 minutes and partitioned betweenchloroform (100 mL) and saturated aqueous sodium carbonate (100 mL). Theorganic layer was separated and washed with brine (100 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica gel(eluting with ethyl acetate) to provide 4.6 g of ethyl1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxylate as a whitesolid.

Part D

The method described in Part C of Example 10 was used to treat ethyl1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxylate (4.6 g, 17mmol) with ammonium hydroxide (100 mL). The solid was isolated byfiltration and washed with water to provide 3.0 g of1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxamide as a whitepowder, which was mixed with material from another run.

Part E

A modification of the method described in Part E of Examples 1-4 wasused to treat1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carboxamide (3.46 g,14.1 mmol) with phosphorous oxychloride (10 mL). The reaction was heatedfor 2.5 hours. After the addition of ammonium hydroxide (35 mL of 28%) aprecipitate formed. The mixture was stirred for 30 minutes, and theprecipitate was isolated by filtration and washed with water to provide3.1 g of 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carbonitrileas a white powder.

Part F

A modification of the method described in Part F of Examples 1-4 wasused to treat a solution of1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carbonitrile (3.1 g, 14mmol) in acetic acid (27 mL) with potassium acetate (2 g, 20 mmol) andbromine (2.2 g, 14 mmol). The reaction was stirred for 20 minutes beforethe addition of aqueous sodium hydrogensulfite (1 mL). After theaddition of saturated aqueous sodium carbonate, a precipitate formed,was isolated by filtration, and washed with water to provide 2.4 g of a2:1 mixture of4-bromo-1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carbonitrileand 1-ethyl-5-(2-methanesulfonylethyl)-1H-pyrazole-3-carbonitrile, whichwas used without purification.

Part G

Triphenylphosphine (6.1 mg, 0.023 mmol) and palladium (II) acetate (1.75mg, 0.0018 mmol) were added to a mixture of the material from Part F,2-aminophenylboronic acid hydrochloride (2.03 g, 11.8 mmol), 2 M aqueoussodium carbonate (23 mL), water (3 mL) and n-propanol (14 mL) accordingto a modification of the method described in Part G of Examples 1-4. Thework-up procedure was carried out by partitioning betweendichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL)and extracting with dichloromethane (50 mL). Following the work-upprocedure, the crude product mixture was triturated with ethyl acetate,and a white solid was removed by filtration. The filtrate wasconcentrated under reduced pressure and purified by columnchromatography on silica gel (eluting with 90:10dichloromethane/methanol) followed by recrystallization fromacetonitrile. The crystals were isolated by filtration, washed withacetonitrile, and dried under vacuum for 20 hours at 60° C. to provide0.05 g of2-ethyl-1-(2-methanesulfonylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine aspale yellow needles, mp 220-222° C.

Anal. Calcd for C₁₅H₁₈N₄O₂S.0.25 H₂O: C, 55.80; H, 5.77; N, 17.35.Found: C, 55.71; H, 5.60; N, 17.41.

Example 132-Methyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-aminetrifluoroacetate

A solution of2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.6 g, 2mmol), prepared as described in Example 3, in trifluoroacetic acid (10mL) was treated with platinum (IV) oxide (0.5 g) and shaken underhydrogen pressure (50 psi, 3.4×10⁵ Pa) for 24 hours. The reactionmixture was diluted with chloroform (20 mL) and filtered through a layerof CELITE filter agent. The filtrate was concentrated under reducedpressure and dissolved in chloroform (50 mL). The solution was adjustedto pH 12 with the addition of ammonium hydroxide and stirred for 20minutes. The organic layer was separated, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resulting solidwas recrystallized from acetonitrile to provide 0.3 g of2-methyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-aminetrifluoroacetate as a white powder, mp 204-206° C.

Anal. Calcd for C₁₅H₂₂N₄.0.76 CF₃COOH: C, 57.51; H, 6.65; N, 16.24.Found: C, 57.11; H, 7.04; N, 16.23.

Example 141,2-Dimethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A modification of the method described in Example 13 was used to reduce1,2-dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.0 g, 4.7 mmol),prepared as described in Example 5. During the work-up procedure, theresidue from the filtrate was suspended in 6 M hydrochloric acid andstirred for 30 minutes. The suspension was adjusted to pH 13 with theaddition of 50% sodium hydroxide. The resulting solid was isolated byfiltration, washed with water, air-dried, and recrystallized fromacetonitrile to provide 0.74 g of1,2-dimethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as anoff-white solid, mp 258-259° C. Anal. Calcd for C₁₂H₁₆N₄.0.1 H₂O: C,66.09; H, 7.49; N, 25.69. Found: C, 65.87; H, N, 25.51.

Example 152-Methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine

Part A

tert-Butyl N-(2-pyridyl)carbamate is available from the literatureprocedure (Moraczewski, A. L. et al, J. Org. Chem., 1998, 63, 7258) orcan be prepared by the following method. Under a nitrogen atmosphere,sodium bis(trimethylsilyl)amide (225 mL of a 1.0 M solution intetrahydrofuran) was added over a period of 20 minutes to a solution of2-aminopyridine (10.61 g, 108.0 mmol) in dry tetrahydrofuran (THF) (150mL). The solution was stirred for 15 minutes and then cooled to 0° C. Asolution of di-tert-butyl dicarbonate (24.60 g, 112.7 mmol) in THF (50mL) was added slowly, and the reaction was allowed to warm to ambienttemperature slowly and stirred overnight. The THF was removed underreduced pressure, and the residue was partitioned between ethyl acetate(500 mL) and 0.1 M hydrochloric acid (250 mL). The organic layer wasseparated; washed sequentially with 0.1 M hydrochloric acid (250 mL),water (250 mL), and brine (250 mL); dried over magnesium sulfate;filtered; and concentrated under reduced pressure. The crude product waspurified by chromatography on a HORIZON HPFC system (65I cartridge,eluting with 80:20 hexanes/ethyl acetate to provide 17.43 g oftert-butyl N-(2-pyridyl)carbamate as a white solid.

Part B

Under a nitrogen atmosphere, a solution of tert-butylN-(2-pyridyl)carbamate (15.71 g, 80.9 mmol) andN,N,N′N′-tetramethylethylenediamine (TMEDA, 25.3 g, 218 mmol) in THF(400 mL) was cooled to −78° C. n-Butyllithium (81 ML of a 2.5 M solutionin hexanes) was added dropwise over a period of 20 minutes. The solutionwas stirred for ten minutes, and then the addition funnel was rinsedwith additional THF (20 mL). The solution was warmed to −6° C., stirredfor two hours, and cooled again to −78° C. Triisopropyl borate (57.7 g,307 mmol) was added over a period of ten minutes. The resulting solutionwas warmed to 0° C. and then poured into saturated aqueous ammoniumchloride (500 mL). A yellow solid formed and was stirred with diethylether (300 mL), isolated by filtration, washed with diethyl ether andwater, and air-dried overnight to provide2-tert-butoxycarbonylamino-3-pyridylboronic acid as a yellow solid.

Part C

A solution of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (7.2 g)and hydrogen chloride (4 M in ethanol) was heated at reflux for 20minutes. Toluene (50 mL) was added, and the solvents were removed bydistillation. The resulting oil was dissolved in water and adjusted topH 8 with the addition of 2 M aqueous sodium carbonate. The resultingsolution was concentrated under reduced pressure to a volume of 20 mL.

Part D

4-Bromo-1-methyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (2.42 g,10.0 mmol), prepared as described in Example 3, solid sodium carbonate(1.6 g, 15 mmol), 1-propanol (25 mL), palladium (II) acetate (22 mg, 0.1mmol), and triphenylphosphine (79 mg, 0.3 mmol) were added to thesolution from Part C, and the reaction was heated at 100° C. under anitrogen atmosphere for 6.5 hours. Additional palladium (II) acetate (22mg, 0.1 mmol) and triphenylphosphine (79 mg, 0.3 mmol) were added, andthe reaction was heated at 100° C. overnight. The work-up proceduredescribed in Part G of Examples 1-4 was followed. The crude product wasobtained as a semi-solid and was stirred with tert-butyl methyl ether toform a solid, which was isolated by filtration. The solid was purifiedby chromatography on a HORIZON HPFC system (40+M cartridge (eluting withacetone/methanol in a gradient from 99:1 to 85:1). The resulting solid(450 mg) was triturated with hot acetonitrile (10 mL), cooled to 0° C.,isolated by filtration, and air-dried to provide 365 mg of2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amineas a white powder, mp >250° C. MS (APCI) m/z 256 (M+H)⁺; Anal. Calcd forC₁₄H₁₇N₅.0.4H₂O: C, 64.05; H, 6.83; N, 26.68. Found: C, 64.04; H, 7.27;N, 26.70.

Example 162-Ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine

Hydrochloric acid (15 mL of 1M) was added to a solution of2-tert-butoxycarbonylamino-3-pyridylboronic acid (3.31 g, 13.9 mmol),prepared as described in Parts A and B of Example 15, in 1-propanol (15mL), and the resulting mixture was heated at 80° C. for one hour andallowed to cool to ambient temperature. Solid sodium carbonate (2.69 g,25.4 mmol) was added with stirring followed by a solution of4-bromo-1-ethyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (1.78 g,6.95 mmol), prepared as described in Example 2, in 1-propanol (4 mL).Triphenylphosphine (109 mg, 0.42 mmol) was added, and the reaction wasevacuated and backfilled with nitrogen three times and stirred for fiveminutes. A solution of palladium (II) acetate (31 mg, 0.14 mmol) in warmtoluene (0.5 mL) was added. The reaction was twice evacuated andbackfilled with nitrogen and then heated at 100° C. overnight. Ananalysis by HPLC indicated the reaction was incomplete, and additionaltriphenylphosphine (109 mg, 0.42 mmol) and palladium (II) acetate (31mg, 0.14 mmol) were added. The reaction was twice evacuated andbackfilled with nitrogen at heated at reflux for three days. The1-propanol was removed under reduced pressure, and the residue wasdissolved in chloroform (100 mL). The resulting solution was washed withwater, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by chromatography on aHORIZON HPFC system as described in Example 15. The resulting solid (200mg) was recrystallized from acetonitrile (20 mL) after hot filtration,isolated by filtration, washed with cold acetonitrile, and driedovernight in a vacuum oven at 60° C. to provide 0.17 g of2-ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amineas off-white needles, mp 273-276° C.

Anal. Calcd for C₁₅H₁₉N₅: C, 66.89; H, 7.11; N, 26.00. Found: C, 66.77;H, 6.94; N, 26.34.

Example 171-(2-Methylpropyl)-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine

A modification of the method described in Example 16 was used to treat2-tert-butoxycarbonylamino-3-pyridylboronic acid (11.33 mmol) in1-propanol (10 mL) with hydrochloric acid (12 mL of 1 M) followed bysodium carbonate (1.99 g, 18.8 mmol),4-bromo-5-(2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile (1.53 g,5.66 mmol, prepared as described in Example 1) in 1-propanol (5 mL),triphenylphosphine (44.5 mg, 0.17 mmol), and palladium (II) acetate (13mg, 0.057 mmol) in toluene (0.25 mL). The reaction was complete after itwas heated overnight. Following the work-up procedure and purification,0.18 g of1-(2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-aminewas obtained as off-white needles, mp 257-260° C.

Anal. Calcd for C₁₆H₂₁N₅: C, 67.82; H, 7.47; N, 24.71. Found: C, 67.77;H, 7.59; N, 24.52.

Example 182-Butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine

A modification of the method described in Example 16 was used to treat2-tert-butoxycarbonylamino-3-pyridylboronic acid (2.98 g, 12.5 mmol) in1-propanol (15 mL) with hydrochloric acid (15 mL of 1 M) followed bysodium carbonate (2.66 g, 25.1 mmol),4-bromo-1-butyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (1.91 g,6.72 mmol, prepared as described in Example 4) in 1-propanol (4 mL),triphenylphosphine (105 mg, 0.400 mmol), and palladium (II) acetate (30mg, 0.13 mmol). The reaction was complete after it was heated over twonights, and no additional reagents were added. Following the work-upprocedure and purification, the crude solid was purified bychromatography on a HORIZON HPFC system (eluting with chloroform/CMA ina gradient from 100:0 to 75:25 to provide 0.48 g of a light yellowsolid, which was recrystallized and isolated as described in Example 16to provide 0.29 g of2-butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amineas off-white needles, mp 219-222° C.

Anal. Calcd for C₁₇H₂₃N₅: C, 66.86; H, 7.80; N, 23.55. Found: C, 68.56;H, 8.05; N, 23.88.

Example 19 1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Under a nitrogen atmosphere, a mixture sodium tert-butoxide (39.0 g,0.406 mol) and ethanol (135 mL) was stirred for 30 minutes; most of thesolid was dissolved. A solution of diethyl oxalate (25.6 mL, 0.189 mol)and 6-chloro-2-hexanone (25.6 mL, 0.189 mol) in ethanol (20 mL) wasadded over a period of 20 minutes. The reaction was stirred at ambienttemperature for one hour, and potassium acetate (28.0 g, 283 mmol) andacetic acid (95 mL of 2 M) were sequentially added. The reaction wascooled to 0° C., and ethylhydrazine oxalate (31.0 g, 208 mmol) was addedin one portion. The reaction was allowed to warm to ambient temperature,stirred for two hours, and then concentrated under reduced pressure.Water was added, and the resulting solution was adjusted to pH 11 withthe addition of 2 M aqueous sodium carbonate. The mixture was extractedwith chloroform; the combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide ethyl5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carboxylate as a yellow oil thatwas used without purification.

Part B

Potassium acetate (92.6 g, 943 mmol), sodium iodide (7.0 g, 47 mmol),and N,N-dimethylformamide (DMF) (943 mL) were added to the material fromPart A, and the reaction was heated at 90° C. for four hours under anitrogen atmosphere and allowed to cool to ambient temperature. Waterwas added, and the resulting mixture was extracted with diethyl ether.The combined extracts were washed with water (3×), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to provideethyl 5-(4-acetoxybutyl)-1-ethyl-1H-pyrazole-3-carboxylate, which wasused without purification.

Part C

A solution of the material from Part B in methanol (150 mL) was treatedwith ammonium hydroxide (150 mL) according to a modification of themethod described in Part D of Examples 1-4. The reaction was heatedovernight at 125° C. and allowed to cool to ambient temperature. Themethanol and some water were removed under reduced pressure, and theremaining solution was extracted with chloroform. The combined extractswere dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide 18.0 g of1-ethyl-5-(4-hydroxybutyl)-1H-pyrazole-3-carboxamide as a dark oil thatwas used without purification.

Part D

A modification of the method described in Part E of Examples 1-4 wasused to treat 1-ethyl-5-(4-hydroxybutyl)-1H-pyrazole-3-carboxamide (18.2g, 86.1 mmol) with phosphorous oxychloride (60 mL). The reaction washeated for three hours before cooling to 0° C. and pouring into icewater. The mixture was adjusted to pH 12 with the addition of 2 Naqueous sodium carbonate and extracted with chloroform. The combinedextracts were passed through a layer of silica gel (eluting first withchloroform and then with 1:1 hexane/ethyl acetate to provide 10.8 g of5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile as a dark oil.

Part E

5-(4-Chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (10.8 g, 51.0 mmol)was treated with potassium acetate (10.0 g, 102 mmol) and bromine (2.9mL, 56 mmol) in acetic acid (102 mL), and the reaction was stirredovernight at ambient temperature. The acetic acid was removed underreduced pressure, and the residue was partitioned between water andchloroform. The mixture was adjusted to pH 10 with the addition of 2 Naqueous sodium carbonate. The aqueous layer was extracted withchloroform, and the combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting yellow oil was purified by chromatography on a HORIZON HPFCsystem (eluting with hexanes/ethyl acetate in a gradient from 95:5 to50:50) to provide4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile.

Part F

2-Aminophenylboronic acid hydrochloride (1.88 g, 10.8 mmol), potassiumphosphate (6.9 g, 32 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (186 mg, 0.18 mmol), andbis[(2-diphenylphosphino)phenyl]ether (116 mg, 0.217 mmol) were added toa solution of4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (2.1 g, 7.2mmol) in toluene (45 mL). Nitrogen was bubbled through the reactionmixture, and then the reaction was heated at 110° C. for 48 hours. Themixture was filtered through a layer of silica gel (eluting with 3:2chloroform/methanol). The filtrate was concentrated under reducedpressure and dissolved in ethanol (36 mL). Hydrogen chloride (5.4 mL ofa 4 M solution in ethanol) was added to the resulting solution, and thereaction was heated at reflux for two hours and allowed to cool toambient temperature. The solvent was removed under reduced pressure, andthe residue was adjusted to pH 11 with the addition of 2 M aqueoussodium carbonate. The mixture was diluted with brine and extracted withchloroform. The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by chromatography on a HORIZON HPFC system (40+M cartridge,eluting with chloroform/CMA in a gradient from 100:0 to 70:30). Theresulting dark semi-solid was recrystallized from acetonitrile toprovide 175 mg of1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a tansolid.

Anal. Calcd for C₁₆H₁₉ClN₄: C, 63.47; H, 6.32; N, 18.50. Found: C,63.80; H, 6.58; N, 18.38.

Example 20N-[4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamide

Methanesulfonamide (1.14 g, 12.0 mmol) was added to a suspension ofsodium hydride (60% dispersion in mineral oil, 480 mg, 12.0 mmol) in DMF(5 mL); the reaction was stirred for five minutes.1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.70 g,2.4 mmol, prepared as described in Example 19) in DMF (2 mL) and sodiumiodide (90 mg, 0.6 mmol) were sequentially added. The reaction washeated at 80° C. for one hour and 90° C. for three hours, allowed tocool to ambient temperature, and poured into ice water (70 mL). Aprecipitate was removed by filtration, and the filtrate was washed withdiethyl ether. A precipitate formed in the aqueous layer over a periodof 24 hours and was isolated by filtration and washed with water toprovide 200 mg ofN-[4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamideas tan crystals, mp 192-194° C.

MS (APCI) m/z 362 (M+H)⁺;

Anal. Calcd for C₁₇H₂₃N₅O₂S: C, 56.49; H1 6.41; N, 19.37. Found: C,56.40; H16.56; N 19.24.

Example 21 4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol

Part A

Potassium acetate (1.69 g, 17.2 mmol), sodium iodide (255 mg, 1.7 mmol),and DMF (17 mL) were added to4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.0 g, 3.4mmol, prepared as described in Parts A-E of Example 19), and thereaction was heated at 100° C. for two hours under a nitrogen atmosphereand allowed to cool to ambient temperature. Water was added, and theresulting mixture was extracted with diethyl ether. The combinedextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The crude product was purifiedby chromatography on a HORIZON HPFC system (40+M cartridge, eluting withhexanes/ethyl acetate in a gradient from 90:10 to 60:40) to provide 0.86g of 4-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)butyl acetate.

Part B

Triphenylphosphine (21 mg, 0.082 mmol), 2-aminophenylboronic acidhydrochloride (710 mg, 4.1 mmol), 2 M aqueous sodium carbonate (4.1 mL),n-propanol (4.8 mL), and water (1 mL) were added to4-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)butyl acetate (0.86 mg, 2.7mmol), and the flask was evacuated and backfilled with nitrogen fivetimes before the addition of palladium (II) acetate (6.0 g, 0.027 mmol).The reaction was evacuated and backfilled with nitrogen three more timesand then heated overnight at 100° C. An analysis by HPLC indicated thatthe reaction was incomplete. Additional triphenylphosphine (10 mg, 0.038mmol), 2-aminophenylboronic acid hydrochloride (300 mg, 1.73 mmol),solid sodium carbonate (500 mg), and palladium (II) acetate (3.0 g,0.013 mmol) were added at ambient temperature, and the reaction washeated at reflux for three hours and allowed to cool to ambienttemperature. The reaction was diluted with brine and extracted withchloroform. The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure. Methanol (10 mL) andsodium methoxide (2.2 mL of a 47% solution in methanol) were added tothe resulting dark oil. The reaction was heated at reflux for threehours, allowed to cool to ambient temperature, and concentrated underreduced pressure. The residue was diluted with water and extracted withchloroform. The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by chromatography on a HORIZON HPFC system (40+M cartridge,eluting with chloroform/CMA in a gradient from 100:0 to 75:25) toprovide an oil. The oil was crystallized from acetonitrile andrecrystallized from acetonitrile to provide 250 mg of4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol asgold-colored crystals, mp 159-160° C.

MS (APCI) m/z 285 (M+H)⁺;

Anal. Calcd for C₁₆H₂₀N₄O: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.32;H, 7.41; N, 19.80.

Example 222-[4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]isoindole-1,3-dione

Part A

Potassium phthalimide (954 mg, 5.15 mmol), sodium iodide (130 mg, 0.86mmol), and DMF (5 mL) were added to4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.0 g, 3.4mmol, prepared as described in Parts A-E of Example 19), and thereaction was heated at 100° C. for 45 minutes under a nitrogenatmosphere and allowed to cool to ambient temperature. Water (50 mL) wasadded, and the resulting mixture was stirred at 0° C. A precipitateformed, was isolated by filtration, and was dissolved in chloroform. Theresulting solution was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. An analysis by nuclear resonancespectroscopy (NMR) indicated that starting material was present. Thesolid was treated with potassium phthalimide (1.27 g, 6.88 mmol), sodiumiodide (130 mg, 0.86 mmol), and DMF (5 mL) and heated at 90° C. forthree hours. Water (50 mL) was added, and the resulting solid wasisolated by filtration to provide 0.97 g of4-bromo-1-ethyl-5-(4-phthalimidobutyl)-1H-pyrazole-3-carbonitrile as agray, crystalline solid.

Part B

4-Bromo-1-ethyl-5-(4-phthalimidobutyl)-1H-pyrazole-3-carbonitrile (0.97g, 2.4 mmol) was treated with 2-aminophenylboronic acid hydrochloride(839 mg, 4.84 mmol), potassium phosphate (2.56 g, 12.1 mmol),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (124 mg, 0.12mmol), and bis[(2-diphenylphosphino)phenyl]ether (75 mg, 0.14 mmol)according to the method described in Part F of Example 19. The reactionwas heated for 24 hours. Following the purification andrecrystallization, 0.157 g of2-[4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]isoindole-1,3-dionewas obtained as brown crystals, mp 216-217° C.

Anal. Calcd for C₂₄H₂₃N₅O₂: C, 69.72; H, 5.61; N, 16.94. Found: C,69.47; H, 5.89; N, 16.94.

Example 23 1-(2-Aminoethyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride

Part A

4-Phthalimido-2-butanone was obtained from the literature procedure,Eriks et al, J. Med. Chem., 1992, 35, 3239-3246. Sodium tert-butoxide(20.75 g, 0.216 mol) was added over a period of 12 minutes to ethanol(160 mL) under a nitrogen atmosphere. When all solids had dissolved,diethyl oxalate (31.55 g, 0.216 mol) and a suspension of4-phthalimido-2-butanone (46.9 g, 0.216 mol) were sequentially added.The reaction was stirred at ambient temperature for 2.5 hours. Aprecipitate was present and was isolated by filtration to provide 37.4 gof ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt as a light orangesolid.

Part B

A modification of the method described in Part A of Example 11 wasfollowed. A solution of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodiumsalt (37.64 g, 0.110 mol) in glacial acetic acid (160 L) was cooled to10° C. before the addition of ethylhydrazine oxalate (16.52 g, 0.110mol). During the addition, the reaction temperature was maintainedbetween 9 and 11° C. The reaction was complete in two hours. The crudeproduct, a reddish-orange oil, was treated with diethyl ether (150 mL)to form a solid, which was isolated by filtration to provide 26.5 g ofethyl 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxylate as a tansolid.

Part C

A solution of ethyl1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxylate (10.0 g, 29.3mmol) in hydrochloric acid (20 mL of 1 M) and acetic acid (60 mL) washeated at 105° C. for 14.5 hours. An analysis by HPLC indicated thepresence of starting material; the reaction was heated at 115° C. forthree hours and cooled to ambient temperature. The reaction was pouredinto ice water (200 mL). A precipitate formed and was isolated byfiltration, washed with water, and dried in the filter funnel for 1.5hours to provide 7.64 g of white solid. Toluene (40 mL) and thionylchloride (20 mL) were added to the white solid, and the mixture washeated at 115° C. for 40 minutes, cooled to ambient temperature, andconcentrated under reduced pressure. Toluene was added and removed underreduced pressure. Dichloromethane (60 mL) was added to the residue, andthe resulting solution was cooled to 0° C. Concentrated ammoniumhydroxide (20 mL) was added, a precipitate formed, and the reaction wasstirred for five minutes. The mixture was concentrated under reducedpressure, and the resulting solid was washed with water twice and driedon the filter funnel. The solid was combined with material from anotherrun and recrystallized from ethanol (45 mL/g) to provide 8.5 g of1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxamide.

Part D

A solution of 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carboxamide(8.5 g, 27.2 mmol) and thionyl chloride (20 mL) in toluene (40 mL) washeated at reflux for five hours, allowed to cool to ambient temperature,and concentrated under reduced pressure. The residue was dissolved inchloroform and made basic with the addition of 2 M sodium carbonate. Theaqueous layer was separated at extracted with chloroform (4×), and thecombined organic fractions were washed with brine. The brine wasextracted with chloroform (4×). The combined organic fractions weredried over magnesium sulfate, filtered, and concentrated under reducedpressure. The crude product (8.08 g) was purified by chromatography on aHORIZON HPFC system (65I cartridge, eluting with chloroform/CMA in agradient from 100:0 to 80:20) to provide 7.73 g of1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile as a whitesolid.

Part E

Potassium acetate (3.9 g, 39.5 mmol) was added to a solution of1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile (7.73 g, 26.3mmol) in acetic acid (37.5 mL) and dichloromethane (75 mL). Bromine(5.88 g, 36.8 mmol) was added, and the reaction was stirred for 14hours. A precipitate was present. Saturated aqueous sodiumhydrogensulfite was added, and the dichloromethane was removed underreduced pressure. Water (500 mL) was added with stirring, and theresulting solid was isolated by filtration, washed with water, and driedon the filter funnel to provide4-bromo-1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile.

Part F

Hydrazine hydrate (4.26 g, 85.1 mmol) was added to a solution of4-bromo-1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile (6.35g, 17.0 mmol) in ethanol, and the solution was heated at reflux for onehour and cooled to ambient temperature. A precipitate formed and wasisolated by filtration and washed with cold ethanol. The filtrate wasconcentrated under reduced pressure, and the resulting white solid wastwice treated with toluene and concentrated under reduced pressure. Thecombined solids were dissolved in 1-methyl-2-pyrrolidinone (NMP) (30mL), and di-tert-butyl dicarbonate (4.37 g, 20.0 mmol) was added. Thereaction was stirred overnight, and additional di-tert-butyl dicarbonate(0.50 g, 2.3 mmol) was added. The reaction was stirred for 25 minutesand cooled to 0° C. Water (350 mL) was added to form a precipitate, andthe mixture was stirred for 30 minutes. The solid was isolated byfiltration, washed with water, and purified by chromatography on aHORIZON HPFC system (651 cartridge, eluting with hexanes/ethyl acetatein a gradient from 60:40 to 40:60) to provide 5.73 g of[2-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)ethyl]tert-butyl carbamateas a white solid.

Part G

2-[(2,2-Dimethylpropanoyl)amino]phenylboronic acid (also known as2-pivaloylaminobenzene)boronic acid) was prepared using the literatureprocedure of Rocca, P. et al, Tetrahedron, 1993, 49,49-64. The methoddescribed in Part G of Examples 1-4 was used to couple[2-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)ethyl]tert-butyl carbamate(5.50 g, 16.0 mmol) and (2-pivaloylaminobenzene)boronic acid (5.3 g, 24mmol) in the presence of palladium (II) acetate (72 mg, 0.32 mmol),triphenylphosphine (252 mg, 0.96 mmol), and 2 M aqueous sodium carbonate(12 mL). After the reaction was heated for nine hours, additionalpalladium (H) acetate (72 mg, 0.32 mmol), triphenylphosphine (252 mg,0.96 mmol), and 2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (1.8g, 8.1 mmol) were added, and the reaction was heated for an additional15 hours. The crude product was purified by chromatography on a HORIZONHPFC system (651 cartridge, eluting with hexanes/ethyl acetate in agradient from 70:30 to 35:65) to provide 4.35 g of tert-butyl2-(3-cyano4-{2-[(2,2-dimethylpropanoyl)amino]phenyl}-1-ethyl-1H-pyrazol-5-yl)ethylcarbamatecontaining small amounts of[2-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)ethyl]tert-butyl carbamateand [2-(5-cyano-2-ethyl-2H-pyrazol-3-yl)ethyl]tert-butyl carbamate.

Part H

A solution of the material from Part G in ethanol (50 mL) was treatedwith sodium tert-butoxide (2 mmol) and heated at 100° C. under anitrogen atmosphere for 3.5 hours. The reaction was allowed to cool toambient temperature, and the ethanol was removed under reduced pressure.The residue was partitioned between chloroform and brine. The aqueouslayer was separated and extracted with chloroform (4×). The combinedorganic fractions were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bychromatography on a HORIZON HPFC system (40+M cartridge, eluting withchloroform/CMA in a gradient from 95:5 to 60:40) to provide 1.71 g of2-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl tert-butylcarbamate as a white solid containing a small amount of hexane.

Part I

Hydrogen chloride (5 mL of a 4 M solution in ethanol) was added to asuspension of 2-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyltert-butyl carbamate (1.71 g) in ethanol (10 mL), and the reaction washeated at reflux for one hour and cooled to ambient temperature. Aprecipitate formed, and the reaction mixture was cooled to 0° C. Thesolid was isolated by filtration and washed with diethyl ether toprovide 1.521 g of1-(2-aminoethyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride.

Examples 23-33

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-aminoethyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride (32 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.068mL, 0.4 mmol) in chloroform (1 mL). The test tubes were capped, shakenfor four hours at ambient temperature, and allowed to stand overnight.Two drops of water were added to each test tube, and the solvent wasremoved by vacuum centrifugation.

The compounds were purified by preparative high-performance liquidchromatography (prep HPLC) using a Waters FractionLynx automatedpurification system. The prep HPLC fractions were analyzed using aMicromass LC/TOF-MS, and the appropriate fractions were combined andcentrifuge evaporated to provide the trifluoroacetate salt of thedesired compound. Column: Zorbax BonusRP, 21.2×50 millimeters (mm), 5micron particle size; non-linear gradient elution from 5 to 95% B whereA is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile; fraction collection by mass-selective triggering. Thetable below shows the reagent added to each test tube, the structure ofthe resulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt. EXAMPLES 23-33

Measured Mass Example Reagent R (M + H) 23 none

256.1570 24 Cyclopropanecarbonyl chloride

324.1846 25 Benzoyl chloride

360.1835 26 Nicotinoyl chloride hydrochloride

361.1784 27 Isopropylsulfonyl chloride

362.1665 28 Dimethylsulfamoyl chloride

363.1611 29 Benzenesulfonyl chloride

396.1493 30 Isopropyl isocyanate

341.2103 31 Phenyl isocyanate

375.1952 32 3-Pyridyl isothiocyanate

392.1692 33 N,N-Dimethylcarbamoyl chloride

327.1965

Example 34 1,2-Dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Triphenylphosphine (0.10 g, 0.45 mmol), 2-aminophenylboronic acidhydrochloride (3.89 g, 22.0 mmol), and4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (prepared as describedin Parts A-C of Example 5, 3.00 g, 15.0 mmol) were placed in a flask.After 1-propanol was added (22 mL), the flask was placed under vacuumand back-filled with nitrogen three times. Palladium (II) acetate (30mg, 0.15 mmol) was added, followed by aqueous sodium carbonate (22.5 mLof 2 M) and water (4.4 mL). The reaction was heated overnight under anitrogen atmosphere at 100 ° C. Additional 2-aminophenylboronic acidhydrochloride (1.0 g), palladium (II) acetate (approximately 10 mg),aqueous sodium carbonate (10 mL of 2 M), and water (5 mL) were added.The reaction was heated at 100° C. for 8 hours, then was allowed to coolto ambient temperature. The reaction mixture was partioned betweendichloromethane and water. The organic layer was concentrated underreduced pressure and the crude product was purified by chromatography ona HORIZON HPFC system (silica gel, gradient elution with 0-30% CMA inchloroform). The appropriate fractions were combined and concentratedunder reduced pressure. The residue was dissolved in dichloromethane andconcentrated under reduced pressure, which resulted in the formation ofa solid. Hexanes were added to the solid, which was isolated byfiltration and crystallized from acetonitrile to yield 0.637 g of1,2-dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white needles,mp >250° C.

¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.1 Hz,1H), 7.32 (t, J=7.2 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 6.60 (br s, 2H),4.07 (s, 3H), 2.80 (s, 3H);

MS (APCI) m/z 213 (M+H)⁺;

Anal. calcd for C₁₂H₁₂N₄.0.19H₂O: C, 66.83; H, 5.79; N, 25.98. Found: C,66.47; H, 5.64; N, 26.02.

Example 35 2-Ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Ethylhydrazine oxalate (23.7 g, 158 mmol) was added slowly to an 11° C.solution of ethyl acetopyruvate (50.0 g, 316 mmol) in ethanol so thatthe internal temperature did not exceed 14° C. The reaction was allowedto warm to ambient temperature and was stirred overnight. The reactionwas concentrated under reduced pressure and 2 M sodium carbonate wasadded to adjust the mixture to pH 9. The mixture was transferred to aseparatory funnel. The aqueous phase was extracted with methyltert-butyl ether (3×600 mL). The organic layers were combined, driedover magnesium sulfate, filtered, and concentrated under reducedpressure to yield 28.94 g of ethyl1-ethyl-5-methyl-1H-pyrazole-3-carboxylate as an orange oil that wasused without purification in the next reaction.

Part B

A mixture of the material prepared in Part A (28.94 g) and concentratedammonium hydroxide (275 mL) was heated at 125° C. for 2 days in apressure vessel. A precipitate formed and was isolated by filtration butwas found to contain a mixture of material. The filtrate was stirred at0° C. for 30 minutes and a white solid formed. The solid was isolated,washed with water, and dried to yield 10.22 g of1-ethyl-5-methyl-1H-pyrazole-3-carboxamide as a white solid.

Part C

1-Ethyl-5-methyl-1H-pyrazole-3-carboxamide (10.2 g, 66.7 mmol) wastreated with phosphorus oxychloride (41 mL) according to the methoddescribed in Part C of Example 8. The crude product was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 1-21% ethyl acetate/hexanes followed by 2-25% CMA in chloroform).The appropriate fractions were combined and concentrated under reducedpressure to yield 8.17 g of 1-ethyl-5-methyl-1H-pyrazole-3-carbonitrileas clear colorless crystals.

Part D

1-Ethyl-5-methyl-1H-pyrazole-3-carbonitrile (2.98 g, 22.0 mmol) wastreated with potassium acetate (4.93 g, 31.0 mmol) and bromine (3.87 g,24.0 mmol) in glacial acetic acid (43 mL) according to the generalmethod described in Part F of Examples 1-4. Methyl tert-butyl ether wasused instead of dichloromethane in the extraction during the work-up.The organic layers were combined and concentrated under reduced pressureto yield 4-bromo-1-ethyl-5-methyl-1H-pyrazole-3-carbonitrile as a whitesolid. Anal. calcd for C₇H₈BrN₃: C, 39.28; H, 3.77; N, 19.63. Found: C,39.30; H, 3.60; N, 19.77.

Part E

4-Bromo-1-ethyl-5-methyl-1H-pyrazole-3-carbonitrile (3.00 g, 14.0 mmol)was treated with triphenylphosphine (0.10 g, 0.42 mmol),2-aminophenylboronic acid hydrochloride (3.64 g, 21.0 mmol), 1-propanol(22 mL), palladium (II) acetate (30 mg, 0.14 mmol), 2 M aqueous sodiumcarbonate (22.5 mL, 45 mmol), and water (4.4 mL) according to thegeneral procedure described in Example 34. The reaction time wasapproximately 18 hours and no additional reagents were added. The crudeproduct mixture was used in the next step without purification.

Part F

A solution of ethanolic HCl, generated from the addition of acetylchloride (1.65 g, 21.0 mmol) to ethanol (21 mL), was added to thematerial from Part E according to a modification of the method describedin Part G of Example 10. The reaction was heated at reflux and thenheated at 81° C. overnight. The reaction mixture was allowed to cool toambient temperature and a white solid was isolated by filtration andstirred in 2 M aqueous sodium carbonate. The mixture was transferred toa separatory funnel where it was extracted with chloroform twice. Theorganic layers were combined, dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The resulting light brown solidwas recrystallized from acetonitrile and isolated to yield 0.564 g of2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine as an off whitepowder, mp 217.0-218.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (dd, J=7.8, 1.2 Hz, 1H), 7.51 (dd,J=8.1, 1.1 Hz, 1H), 7.34 (td, J=7.6, 1.5 Hz, 1H), 7.21 (td, J=7.5, 1.3Hz, 1H), 6.65 (br s, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.82 (s, 3H), 1.43 (t,J=7.2 Hz, 3H);

MS (APCI) m/z 227 (M+H)⁺;

Anal. calcd for C₁₃H₁₄N₄: C,69.00; H,6.24; N, 24.76. Found: C, 68.69; H,6.21; N, 24.81.

Example 36 2-Benzyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Benzylhydrazine dihydrochloride (123.3 g, 0.632 mol) was added inbatches to a 12° C. solution of ethyl acetopyruvate (100.0 g, 0.632 mol)and potassium acetate (155.1 g, 1.58 mol) in glacial acetic acid (1.044L) so that the internal temperature did not exceed 16° C. The coolingbath was removed and the reaction was allowed to stir overnight atambient temperature. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to yield an orange oil to which 2 Maqueous sodium carbonate was added until pH 9 was reached. The mixturewas extracted with methyl tert-butyl ether (3×1 L). The combined organiclayers were dried over magnesium sulfate, filtered, and concentrated toyield 102.5 g of slightly impure ethyl1-benzyl-5-methyl-1H-pyrazole-3-carboxylate.

Part B

A mixture of ethyl 1-benzyl-5-methyl-1H-pyrazole-3-carboxylate (57.57 g,0.236 mol), concentrated ammonium hydroxide (114 mL), and methanol (114mL) was heated at 125° C. for 39 hours in a pressure vessel. Aftercooling to ambient temperature, the vessel was placed in an ice bath andthe reaction solution was stirred for 30 minutes until a precipitateformed. The precipitate was isolated by filtration and washed with waterto yield 28.22 g of 1-benzyl-5-methyl-1H-pyrazole-3-carboxamide.

Part C

1-Benzyl-5-methyl-1H-pyrazole-3-carboxamide (28.22 g, 0.131 mol) wastreated with phosphorus oxychloride (112 mL) according to the generalmethod described in Part C of Example 8. The mixture was heated for 3hours at 90° C. The crude product was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution with 1-25% ethylacetate in hexanes). The appropriate fractions were combined, dried overmagnesium sulfate, and concentrated under reduced pressure to yield 3.38g of 1-benzyl-5-methyl-1H-pyrazole-3-carbonitrile as a white solid.

Part D

1-Benzyl-5-methyl-1H-pyrazole-3-carbonitrile (3.38 g, 17.1 mmol) wastreated with potassium acetate (2.35 g, 24.0 mmol) and bromine (3.01 g,18.9 mmol) in glacial acetic acid (48 mL) according to the methoddescribed in Part F of Examples 1-4. After the 2 M aqueous sodiumcarbonate was added in the work-up, a white solid was isolated byfiltration and washed with water to yield 4.49 g of1-benzyl-4-bromo-5-methyl-1H-pyrazole-3-carbonitrile.

Anal. calcd for C₁₂H₁₀BrN₃: C, 52.20; H, 3.65; N, 15.22. Found: C,51.98; H, 3.45; N, 15.27.

Part E

1-Benzyl-4-bromo-5-methyl-1H-pyrazole-3-carbonitrile (3.00 g, 10.9 mmol)was treated with triphenylphosphine (85 mg, 0.32 mmol),2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (prepared asdescribed in Part G of Example 23, 2.15 g, 16.3 mmol), 1-propanol (22mL), palladium (II) acetate (24 mg, 0.11 mmol), aqueous sodium carbonate(6.5 mL of 2 M, 13 mmol), and water (4.4 mL) according to the generalprocedure described in Example 34. The reaction time was approximately16 hours and no additional reagents were added. The reaction was allowedto cool to ambient temperature and methyl tert-butyl ether (25 mL) wasadded. After the mixture was stirred for about 10 minutes, the layerswere separated. The organic layer was dried over magnesium sulfate,filtered, and concentrated to yield a brown oil. The crude product waspurified by chromatography on a HORIZON HPFC system (silica gel,gradient elution 1-30% ethyl acetate in hexanes). The appropriatefractions were combined, dried over magnesium sulfate, filtered, andconcentrated to yield 2.40 g ofN-[2-(1-benzyl-3-cyano-5-methyl-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamideas an oil that solidified upon standing at ambient temperature.

Part F

A solution ofN-[2-(1-benzyl-3-cyano-5-methyl-1H-pyrazol4-yl)phenyl]-2,2-dimethylpropanamide(2.40 g, 6.44 mmol) and sodium tert-butoxide (0.743 g, 7.73 mmol) inethanol (28 mL) was heated at reflux for 1 day, then was allowed to coolto ambient temperature. A precipitate formed that was isolated byfiltration and washed with water followed by water/ethanol (8:1) toprovide 1.33 g of 2-benzyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp>250° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (dd, J=7.9,1.2 Hz, 1H), 7.51 (dd,J=8.1, 1.1 Hz, 1H), 7.38-7.28 (m, 4H), 7.21-7.15 (m, 3H), 6.70 (br s,2H), 5.70 (br s, 2H), 2.77 (s, 3H); MS (APCI) m/z 289 (M+H)⁺;

Anal. calcd for C₁₈H₁₆N₄: C, 74.98; H, 5.59; N, 19.43. Found: C, 74.80;H, 5.65; N, 19.55.

Examples 37-39

Part A

Diethyl oxalate and 4,4-dimethyl-2-pentanone were treated with sodiumtert-butoxide in ethanol according to the procedure described in Part Aof Examples 14. The product was isolated, washed with ethanol, and driedunder vacuum to provide ethyl 4-hydroxy-6,6-dimethyl-2-oxohept-3-enoate,sodium salt as a white solid.

Part B

A hydrazine reagent from the table below (1 equivalent) was added slowlyto a 11° C. stirred 0.65 M solution of ethyl4-hydroxy-6,6-dimethyl-2-oxohept-3-enoate, sodium salt (1 equivalent) inglacial acetic acid such that the internal temperature did not exceed14° C. In Example 38, the acetic acid solution also contained potassiumacetate (1.5 equivalents). When the addition was complete, the ice bathwas removed and the reaction was allowed to stir overnight at ambienttemperature. The solution was concentrated under reduced pressure. Tothe resulting oil was added 2 M aqueous sodium carbonate the mixturereached pH 9. The mixture was extracted with methyl tert-butyl etherthree times.

The combined organic layers were dried over magnesium sulfate, filtered,and concentrated to yield an oil.

Part C

The material from Part B (37.8-45.4 g, 169-190 mmol) in a 1:1 mixture ofconcentrated ammonium hydroxide/methanol (150-200 mL) was heated at 125°C. for 24 hours in a pressure vessel. After cooling to ambienttemperature, the vessel was placed in an ice bath. The reaction mixturewas stirred for 30 minutes and a precipitate formed. The precipitate wasisolated by filtration and washed with water to yield a carboxamide.

Part D

A mixture of the carboxamide (7.05-13.27 g, 29.7-63.5 mmol) andphosphorous oxychloride (28-52 mL) was heated at 90° C. for 3 hours. Themixture was allowed to cool to ambient temperature and was poured ontoice water (360-680 mL). Additional ice was added. Concentrated ammoniumhydroxide was added to adjust the mixture to pH 8-9. The mixture wasextracted with methyl tert-butyl ether. The organic layers werecombined, dried over magnesium sulfate, filtered, and concentrated underreduced pressure to provide an oil.

Part E

Potassium acetate (1.4 equivalents) followed by bromine (1.1equivalents) were added to a 0.4 M solution of the material from Part Din acetic acid. The reaction was stirred for 18-72 hours at ambienttemperature. Saturated aqueous sodium hydrogensulfite was added toreduce the residual bromine. The mixture was concentrated under reducedpressure and 2 M aqueous sodium bicarbonate was added to adjust themixture to pH 9. A white solid formed and was isolated by filtration andwashed with water to provide a1-alkyl-4-bromo-5-(2,2-dimethylpropyl)-1H-pyrazole-3-carbonitrile.

Example 38:4-Bromo-1-ethyl-5-(2,2-dimethylpropyl)-1H-pyrazole-3-carbonitrile wasobtained as a white solid.

Anal. calcd for C₁₁H₁₆BrN₃: C, 48.90; H, 5.97; N, 15.55. Found: C,48.88; H, 6.26; N, 15.52.

Example 39:4-Bromo-1-butyl-5-(2,2-dimethylpropyl)-1H-pyrazole-3-carbonitrile wasobtained as a white solid.

Anal. calcd for C₁₃H₂₀BrN₃: C, 52.36; H, 6.76; N, 14.09. Found: C,52.06; H, 7.02; N, 13.78.

Part F

Triphenylphosphine (0.03 equivalent), 2-aminophenylboronic acidhydrochloride (1.5-2.0 equivalents), and the material from Part E (1equivalent) were placed in a flask. After 1-propanol was added (so thatthe concentration of material from Part E was 0.55 M), the flask wasplaced under vacuum and back-filled with nitrogen three times. Palladium(II) acetate (0.01 equivalent) was added, followed by 2 M aqueous sodiumcarbonate (3 equivalents) and water (1/5 of the amount of 1-propanol).The reaction was heated overnight under a nitrogen atmosphere at 100° C.The reaction was allowed to cool to ambient temperature and methyltert-butyl ether was added. After the mixture was stirred for about 10minutes, the layers were separated. The organic layer was dried overmagnesium sulfate, filtered, and concentrated to yield a brown oil. InExamples 37 and 38 the oil was used directily in the next step. InExample 39, the crude product was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution with 0-20% ethylacetate in hexanes). The appropriate fractions were combined, dried overmagnesium sulfate, filtered, and concentrated to yield an oil.

Part G

The oil prepared in Part F was converted into a2-alkyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine usingthe general procedure described in Part H of Examples 1-4.

Example 37:2-Methyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine wasisolated as an off-white powder, mp 254.0-255.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (dd, J=7.9, 1.1 Hz, 1H), 7.50 (dd,J=8.1, 1.2 Hz, 1H), 7.31 (td, J=7.1, 1.3 Hz, 1H), 7.17 (td, J=8.1, 1.4Hz, 1H), 6.67 (br s, 2H), 4.10 (s, 3H), 3.25 (s, 2H), 1.02 (s, 9H);

MS (APCI) m/z 269 (M+H)⁺;

Anal. calcd for C₁₆H₂₀N₄: C, 71.61; H, 7.51; N, 20.88. Found: C, 71.37;H, 7.50; N, 21.04.

Example 38: No chromatographic purification was necessary. Aftercrystallization from acetonitrile,2-ethyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine wasisolated as a off-white needles, mp 239.8-240.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (dd, J=8.0, 1.2 Hz, 1H), 7.48 (dd,J=8.1, 1.3 Hz, 1H), 7.30 (dt, J=7.1, 1.4 Hz, 1H), 7.16 (dt, J=8.0, 1.4Hz, 1H), 6.61 (br s,2H), 4.43 (q, J=7.1 Hz, 2H), 3.26 (br s, 2H), 1.46(t, J=7.1 Hz, 3H), 1.01 (s, 9H).

Anal. calcd for C₁₇H₂₂N₄: C, 72.31; H, 7.85; N, 19.84. Found: C, 71.94;H, 8.01; N, 19.80.

Example 39: No chromatography or crystallization steps necessary.2-Butyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine wasisolated as a white powder, mp 163.0-164.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (dd, J=7.9, 0.7 Hz, 1H), 7.49 (dd,J=8.1, 1.0 Hz, 1H), 7.30 (td, J=8.1, 1.1 Hz, 1H), 7.16 (td, J=8.0, 1.1Hz, 1H), 6.62 (br s, 2H), 4.39 (t, J=6.9 Hz, 2H), 3.27 (br s, 2H), 1.87(pentet, J=7.2 Hz, 2H), 1.28 (sextet, J=7.5 Hz, 2H), 1.00 (s, 9H), 0.89(t, J=7.3 Hz, 3H);

MS (APCI) m/z 311 (M+H)⁺;

Anal. calcd for C₁₉H₂₆N₄: C, 73.51; H, 8.44; N, 18.05. Found: C, 73.34;H, 8.21; N, 18.19. EXAMPLES 37-39

Example Hydrazine reagent in Part B R 37 Methylhydrazine —CH₃ 38Ethylhydrazine oxalate —CH₂CH₃ 39 Butylhydrazine oxalate —CH₂CH₂CH₂CH₃

Examples 40-42

Part A

Diethyl oxalate and benzylacetone were treated with sodium tert-butoxidein ethanol according to the procedure described in Part A of Examples1-4. The reaction solution was stirred for 90 minutes and a precipitateformed. The precipitate was isolated to provideethyl-4-hydroxy-2-oxo-6-phenylhex-3-enoate, sodium salt as a whitesolid.

Part B

A hydrazine reagent from the table below (1 equivalent) was added to asolution of ethyl-4-hydroxy-2-oxo-6-phenylhex-3-enoate, sodium salt (1equivalent) in glacial acetic acid according to the procedure describedin Part B of Examples 37-39. The product was isolated as an oil.

Part C

The material from Part B was treated with a 1:1 mixture of concentratedammonium hydroxide/methanol (150-200 mL) according to the proceduredescribed in Part C of Examples 37-39 to yield a carboxamide. Example 40was heated for 2 days, Example 41 was heated for 18 hours, and Example42 was heated for 1 day.

Part D

The carboxamide from Part C was treated with phosphorous oxychlorideaccording to the procedure described in Part D of Examples 37-39 toyield the nitrile as an oil.

Part E

The material from Part D was brominated according to the proceduredescribed in Part E of Examples 37-39. During the work-up in Examples 41and 42, the mixture at pH 9 was extracted with methyl tert-butyl ethertwice. The organic layers were combined, dried over magnesium sulfate,and concentrated to give a brown oil.

Part F

The material from Part E (3.00 g) was treated with triphenylphosphine(0.03 equivalent), 2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid(prepared as described in Part G of Example 23, 1.5 equivalents),1-propanol (22 mL), palladium (II) acetate (0.01 equivalent), 2 Maqueous sodium carbonate (1.2 equivalents), and water (4.4 mL) accordingto the general procedure described in Examples 37-39. The crude productwas purified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 0-25% ethyl acetate in hexanes) to yield an oil.

Part G

To a 0.2 M solution of the material from Part F in ethanol was addedsodium tert-butoxide (1.2 equivalents). The solution was heated atreflux for 1 day, then was allowed to cool to ambient temperature. Aprecipitate formed that was isolated by filtration and washed with asmall amount of water and ethanol. The solid was dried at 70° C. in avacuum oven overnight to provide the product products listed below.

Example 40:2-Methyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine wasisolated as pale yellow powder, mp 210.5-212.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (dd, J=7.8, 0.9 Hz, 1H), 7.53 (dd,J=8.1, 1.0 Hz, 1H), 7.37-7.15 (m, 7H), 6.67 (br s, 2H), 3.77 (s, 3H),3.51 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.5 Hz, 2H);

MS (APCI) m/z 303 (M+H)⁺;

Anal. calcd for C₁₉H₁₈N₄.0.17H_(2l O: C,) 74.71; H, 6.05; N, 18.34.Found: C, 74.40; H, 5.83; N, 18.31.

Example 41: 2-Ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-aminewas isolated as a white powder, mp 179.0-181.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (dd, J=7.8, 1.1 Hz, 1H), 7.53 (dd,J=8.1, 1.2 Hz, 1H), 7.37-7.20 (m, 7H), 6.65 (br s, 2H), 4.17 (q, J=7.2Hz, 2H), 3.53 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.7 Hz, 2H), 1.32 (t, J=7.2Hz, 3H);

Anal. calcd for C₂₀H₂₀N₄: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.71;H, 6.75; N, 17.82.

Example 42:1-(2-Phenylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine wasisolated as a white powder, mp 175.0-176.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (dd, J=7.8, 1.1 Hz, 1H), 7.54 (dd,J=8.1, 1.2 Hz, 1H), 7.37-7.20 (m, 7H), 6.65 (br s, 2H), 4.07 (t, J=7.2Hz, 2H), 3.53 (t, J=7.4 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 1.75 (sextet,J=7.3 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H);

Anal. calcd for C₂₁H₂₂N₄: C, 76.33; H, 6.71; N, 16.96. Found: C, 76.10;H, 6.69; N, 16.90. EXAMPLES 40-42

Example Hydrazine reagent in Part B R 40 Methylhydrazine —CH₃ 41Ethylhydrazine oxalate —CH₂CH₃ 42 Propylhydrazine oxalate —CH₂CH₂CH₃

Example 43 1-Butyl-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Diethyl oxalate and 2-hexanone were treated with sodium tert-butoxide inethanol according to the procedure described in Part A of Examples 1-4.The reaction solution was stirred for 90 minutes and a precipitateformed. The precipitate was isolated to provide1-ethoxy-1,2-dioxooct-3-en-4-olate, sodium salt as a white solid.

Part B

1-Ethoxy-1,2-dioxooct-3-en-4-olate, sodium salt (332.8 g, 1.50 mol) wastreated with tert-butylhydrazine hydrochloride (186.6 g, 1.50 mol)according to the procedure described in Part B of Examples 37-39 toyield ethyl 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxylate as a brownoil.

Part C

Ethyl 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxylate (60 g, 0.24 mol) ina 1:1 mixture of concentrated ammonium hydroxide/methanol (238 mL) washeated at 125° C. for 37 hours in a pressure vessel. After cooling toambient temperature, the vessel was placed in an ice bath. The reactionmixture was stirred for 30 minutes, then was concentrated under reducedpressure to a brown oil. The oil was dissolved in dichloromethane andthe solution was washed with water and brine. The organic layer wasdried over magnesium sulfate, filtered, and concentrated under reducedpressure to give a wet brown solid. Hexanes were added, the mixture wasstirred, and 18.67 g of 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxamidewas isolated by filtration as an off-white solid.

Part D

A solution of trifluoroacetic anhydride (13.5 mL, 95.4 mmol) indichloromethane (84 mL) was added over 15 minutes to a 0° C. solution of5-butyl-1-tert-butyl-1H-pyrazole-3-carboxamide (18.7 g, 86.7 mmol) andtriethylamine (36.3 mL, 260 mmol) in dichloromethane (167 mL). Thereaction was allowed to stir for 10 minutes before the ice bath wasremoved. The reaction was stirred at ambient temperature for 1 hour andthen 2 M aqueous sodium carbonate was added. The mixture was transferredto a separatory funnel and was extracted with dichloromethane threetimes. The combined organic layers were dried over magnesium sulfate,filtered, and concentrated. The crude product was purified bychromatography on a HORIZON HPFC system (silica gel, eluted with 20%ethyl acetate in hexanes). The appropriate fractions were combined,dried over magnesium sulfate, and concentrated under reduced pressure toyield 11.00 g of 5-butyl-1-tert-butyl-1H-pyrazole-3-carbonitrile as anorange oil.

Part E

5-Butyl-1-tert-butyl-1H-pyrazole-3-carbonitrile (11.00 g, 53.6 mmol) wasconverted into 4-bromo-5-butyl-1-tert-butyl-1H-pyrazole-3-carbonitrileusing the procedure described in Part E of Examples 37-39.

Part F

4-Bromo-5-butyl-1-tert-butyl-1H-pyrazole-3-carbonitrile (3.0 g, 10.6mmol) was treated with triphenylphosphine (0.085 g, 0.32 mmol),2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (prepared asdescribed in Part G of Example 23, 2.41 g, 15.8 mmol), 1-propanol (22mL), palladium (II) acetate (0.024 g, 0.11 mmol), 2 M aqueous sodiumcarbonate (6.5 mL, 13.0 mmol), and water (4.4 mL) according to thegeneral procedure described in Examples 37-39. The crude product waspurified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 0-25% ethyl acetate in hexanes) to yield 1.63 g ofN-[2-(5-butyl-1-tert-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamideas an oil.

Part G

To a solution ofN-[2-(5-butyl-1-tert-butyl-3-cyano-1H-pyrazol4-yl)phenyl]-2,2-dimethylpropanamide(1.63 g, 4.28 mmol) in ethanol was added sodium tert-butoxide (0.494 g,5.14 mmol). The solution was heated at reflux for 1 day, then wasallowed to cool to ambient temperature. A precipitate formed that wasisolated by filtration and washed with a small amount of water (24 mL)and ethanol (3 ML) to yield 0.4667 g of1-butyl-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as off-whitecrystals, mp 222.0-223.0° C.

¹H NMR (300 MHz, DMSO-d₆ at 46° C.) δ 7.83 (dd, J=7.9, 1.1 Hz, 1H), 7.50(dd, J=8.1, 1.3 Hz, 1H), 7.34 (td, J=7.2, 1.4 Hz, 1H), 7.23 (td, J=7.9,1.4 Hz, 1H), 6.52 (br, s 2H), 3.39-3.34 (m, 2H), 1.76 (s, 9H), 1.72-1.56(m, 4H), 1.01 (t, J=7.1 Hz, 3H);

MS (APCI) m/z 297 (M+H)⁺;

Anal. calcd for C₁₈H₂₄N₄: C, 72.94; H, 8.16; N, 18.90. Found: C, 72.67;H, 8.29; N, 19.01.

Example 44 1-Ethyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A solution of ethyl 2,4-dioxohexanoate (0.464 mol), prepared asdescribed in Part A of Example 10, in glacial acetic acid (300 mL) wascooled to 0° C. Hydrazine (8.91 g, 0.278 mol) was added dropwise. Thereaction was allowed to warm to ambient temperature, stirred overnight,and concentrated under reduced pressure. The residue was adjusted to pH10 with the addition of 2 M aqueous sodium carbonate. The mixture wasextracted with chloroform (3×250 mL). The combined organic layers weredried over sodium sulfate, filtered, and concentrated under reducedpressure to provide 27.0 g of ethyl 5-ethyl-1H-pyrazole-3-carboxylate,which was used without purification.

Part B

Propyl iodide (0.43 mL, 4.46 mmol) and a solution of sodium ethoxide inethanol (21%, 0.95 g, 3.27 mmol) were added to a solution of ethyl5-ethyl-1H-pyrazole-3-carboxylate (0.5 g, 2.97 mmol) in ethanol (5 mL)at ambient temperature. The reaction was stirred overnight, andadditional propyl iodide (0.05 mL) and sodium ethoxide in ethanol (21%,0.1 g) were added. After 3 hours, the solvent was removed under reducedpressure and the residue was partitioned between an aqueous sodiumchloride solution and methyl tert-butyl ether. The aqueous phase wasextracted with methyl tert-butyl ether twice. The organic phases werecombined, dried over sodium sulfate, filtered, and concentrated underreduced pressure to yield impure ethyl5-ethyl-1-propyl-1H-pyrazole-3-carboxylate.

Part C

Ethyl 5-ethyl-1-propyl-1H-pyrazole-3-carboxylate (13.0 g, 62 mmol) in a4:1 mixture of concentrated ammonium hydroxide/methanol (50 mL) washeated at 125° C. for 18 hours in a pressure vessel. After cooling toambient temperature, the contents of the vessel were poured into a flaskand a precipitate formed immediately. The precipitate was isolated byfiltration to yield 5.02 g of analytically pure5-ethyl-1-propyl-1H-pyrazole-3-carboxamide as off-white crystals, mp105-106° C. MS (APCI) m/z 182.1 (M+H)⁺; Anal. calcd for C₉H₁₅N₃O: C,59.64; H, 8.34; N, 23.19. Found: C, 59.59; H, 8.54; N, 23.39. Anadditional 0.50 g of product was obtained in the second crop from thefiltrate.

Part D

5-Ethyl-1-propyl-1H-pyrazole-3-carboxamide (5.50 g, 30.35 mmol) wastreated with phosphorous oxychloride (20 mL) according to the proceduredescribed in Part D of Examples 37-39 to yield 4.89 g of5-ethyl-1-propyl-1H-pyrazole-3-carbonitrile as an oil.

Part E

5-Ethyl-1-propyl-1H-pyrazole-3-carbonitrile (4.89 g, 30.0 mmol) wasdissolved in glacial acetic acid (30 mL) and treated with potassiumacetate (4.41 g, 44.9 mmol) and bromine (4.79 g, 30.0 mmol). During theslow addition of bromine, an exotherm occurred and and ice bath was usedto cool the reaction. After the addition of bromine was complete, thereaction was allowed to warm to ambient temperature and stir for 5hours. Saturated aqueous sodium hydrogensulfite was added to reduce theresidual bromine. The mixture was concentrated under reduced pressureand 2 M aqueous sodium carbonate was added to adjust the mixture to pH9. The mixture was extracted with chloroform (3×100 mL). The organiclayers were combined, dried over sodium sulfate, filtered, andconcentrated to yield 6.12 g of4-bromo-5-ethyl-1-propyl-1H-pyrazole-3-carbonitrile as a yellow oil.

Part F

A mixture of 4-bromo-5-ethyl-1-propyl-1H-pyrazole-3-carbonitrile (4.00g, 16.5 mmol), 2-aminophenylboronic acid hydrochloride (4.30 g, 24.8mmol), triphenylphosphine (0.26 g, 0.99 mmol), palladium (II) acetate(0.074 g, 0.33 mmol), 2 M aqueous sodium carbonate (24.8 mL, 49.5 mmol),1-propanol (35 mL), and water (5 mL) was heated at reflux for 18 hours.Additional triphenylphosphine (0.26 g) and palladium (I) acetate (0.074g) were added and the mixture was heated at reflux for 22 hours. Themixture was allowed to cool to ambient temperature and methyl tert-butylether (100 mL) was added. The mixture was transferred to a separatoryfunnel and the organic layer was isolated and washed with water andbrine. The aqueous layers were combined and back-extracted with methyltert-butyl ether (2×40 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated to provide a red oil thatwas used in the next step without purification.

Part G

The oil prepared in Part F was converted into1-ethyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine using the generalprocedure described in Part H of Examples 1-4.1-Ethyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.34 g) wasisolated an off-white solid, mp 219-220° C.

¹H-NMR (300 MHz, DMSO-d₆) δ 7.91 (dd, J=7.8, 1.1 Hz, 1H), 7.50 (dd, J=8.1, 1.1 Hz, 1H), 7.37-7.27 (m, 1H), 7.25-7.15 (m, 1H), 6.64 (br s,2H), 4.34 (t, J=7.2 Hz, 2H), 3.25 (q, J=7.5 Hz, 2H), 1.92 (sextet, J=7.3Hz, 2H), 1.29 (t, J=7.5 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H);

¹³C-NMR (75 MHz, DMSO-d₆) δ 150.5, 143.7, 139.0, 135.5, 125.5, 121.6,119.6, 116.0, 50.7, 23.6, 18.2, 13.1, 10.9.

MS (APCI) m/z 255.2 (M+H)⁺;

Anal. calcd for C₁₅H₁₈N₄: C, 70.84; H, 7.13; N, 22.03. Found: C, 70.49;H, 7.38; N, 22.12.

Example 45 2-Butyl-1-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A solution of ethyl 2,4-dioxohexanoate (approximately 60% pure, 45.0 g,0.232 mol), prepared as described in Part A of Example 10, in glacialacetic acid (150 mL) was cooled to 0° C. Butylhydrazine oxalate (25.0 g,0.139 mol) was added slowly. The reaction was allowed to warm to ambienttemperature, stirred overnight, and concentrated under reduced pressure.The residue was adjusted to pH 10 with the addition of 2 M aqueoussodium carbonate. The mixture was extracted with chloroform and anemulsion that contained solid material formed. The solid was isolated byfiltration, and the filtrate was transferred to the separatory funnel.The organic layer was separated. The aqueous layer was extracted withchloroform three times. The combined organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide an oil that was purified by chromatography on a HORIZON HPFCsystem (silica gel, gradient elution with CMA in chloroform) to yield13.27 g of ethyl 5-ethyl-1-butyl-1H-pyrazole-3-carboxylate as a yellowoil.

Part B

Ethyl 5-ethyl-1-butyl-1H-pyrazole-3-carboxylate (13.27 g, 59.2 mmol) inconcentrated ammonium hydroxide (50 mL) was heated at 125° C. for 14hours in a pressure vessel. After the vessel was allowed to cool toambient temperature, methanol (40 mL) was added and the vessel washeated at 125° C. for 1 day. After cooling to ambient temperature, thevessel was cooled in an ice bath and the product began to crystallizefrom the reaction mixture. Two crops of crystals were isolated toprovide 5.50 g of 5-ethyl-1-butyl-1H-pyrazole-3-carboxamide as off-whitecrystals, mp 60-61° C. MS (APCI) m/z 196.1 (M+H)⁺; Anal. calcd forC₁₀H₁₇N₃O: C, 61.51; H, 8.78; N, 21.52.

Found: C, 61.32; H, 9.04; N, 21.71.

Part C

5-Ethyl-1-butyl-1H-pyrazole-3-carboxamide (5.44 g, 27.9 mmol) wastreated with phosphorous oxychloride (20 mL) according to the proceduredescribed in Part D of Examples 37-39 to yield 5.20 g of an oil.Chloroform was used in place of methyl tert-butyl ether in the work-up.

Part D

Potassium acetate (4.11 g, 41.9 mmol) followed by bromine (4.46 g, 27.9mmol) were added to a cooled solution of the material from Part C inacetic acid (35 mL). The reaction was stirred for 48 hours at ambienttemperature. The solution was concentrated under reduced pressure and 2M aqueous sodium bicarbonate was added to adjust the mixture to pH 9-10.The mixture was extracted with methyl tert-butyl ether (250 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure to yield 5.87 g of4-bromo-1-butyl-5-ethyl-1H-pyrazole-3-carbonitrile as a yellow oil thatwas used in the next step without purification.

Part E

A flask containing a mixture of4-bromo-1-butyl-5-ethyl-1H-pyrazole-3-carbonitrile (2.56 g, 10 mmol),2-[(2,2-dimethylpropanoyl)amino]phenylboronic acid (2.87 g, 15 mmol),triphenylphosphine (0.079 g, 0.30 mmol), 2 M aqueous sodium carbonate(15 mL, 30 mmol), water (3 mL) and 1-propanol (20 mL) was placed undervacuum and back-filled with nitrogen three times. Palladium (II) acetate(0.023 g, 0.10 mmol) was added. Again, the flask was placed under vacuumand back-filled with nitrogen. The mixture was heated overnight under anitrogen atmosphere at 100° C. The reaction was allowed to cool toambient temperature and methyl tert-butyl ether was added. After themixture was stirred for about 10 minutes, the layers were separated. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated to yield a brown oil. Hexanes were added to the brown oil,causing the formation of a tan solid that was isolated by filtration.The filtrate was concentrated to an oil that was purified bychromatography on a HORIZON HPFC system (silica gel, eluted with ethylacetate/hexanes) to provide 0.45 g ofN-[2-(5-ethyl-1-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide,which was used in the next step without further purification.

Part F

To a solution ofN-[2-(5-ethyl-1-butyl-3-cyano-1H-pyrazol-4-yl)phenyl]-2,2-dimethylpropanamide(0.45 g, 1.28 mmol) in ethanol (8 mL) was added sodium ethoxide inethanol (21 wt % solution in ethanol, 1.03 g, 3.19 mmol). The solutionwas heated at reflux overnight, then was allowed to cool to ambienttemperature. The solvent was removed under reduced pressure and theresidue was triturated with water. A precipitate formed that wasisolated by filtration and washed with water, then was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-35% CMA in chloroform) to yield 0.14 g of1-ethyl-2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a whitecrystalline solid, mp 215-216° C.

¹H-NMR (300 MHz, DMSO-d₆) δ 7.90 (dd, J=7.8, 1.2 Hz, 1H), 7.49 (dd,J=8.1, 1.1 Hz, 1H), 7.37-7.27 (m, 1H), 7.24-7.16 (m, 1H), 6.63 (br s,2H), 4.37 (t, J=7.3 Hz, 2H), 3.25 (q, J=7.5 Hz, 2H), 1.93-1.80 (m, 2H),1.43-1.30 (m, 2H), 1.29 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H);

¹³C-NMR (75 MHz, DMSO-d₆) δ 150.5, 143.7, 138.8, 135.4, 125.5, 121.6,119.6, 116.0, 49.0, 32.3, 19.3, 18.3, 13.5, 13.1;

MS (APCI) m/z 269.3 (M+H)⁺;

Anal. calcd for C₁₆H₂₀N₄: C, 71.61; H, 7.51; N, 20.88. Found: C, 71.5;H, 7.54; N, 20.94.

Example 46 1-(4-Chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Ethyl 5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carboxylate was preparedusing a modification of the procedure described in Part A of Example 19.Propylhydrazine oxalate was used instead of ethylhydrazine oxalate.After all the reagents were added, the reaction mixture was stirredovernight instead of two hours. Crude ethyl5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carboxylate was isolated as animpure brown oil, MS (APCI) m/z 273.1 (M+H)⁺.

Part B

To a solution of the material from Part A (85.05 g, 0.312 mol) inethanol (500 mL) was added 6 M aqueous sodium hydroxide (104 mL, 0.624mol). The solution was stirred at ambient temperature for 2 hours. Theethanol was removed under reduced pressure and water (200 mL) was added.The aqueous solution was transferred to a separatory funnel and washedwith diethyl ether (100 mL). The aqueous layer was acidified with 6 Maqueous hydrochloric acid to pH 3, causing a precipitate to form. After10 minutes, the precipitate was isolated by filtration, washed withwater, and dried under vacuum at 60° C. overnight to yield 57.1 g of abrown oil which was used without purification in the next step.

Part C

To a solution of the material from Part B (57.1 g, 0.233 mmol) indichloromethane (600 mL) at 0° C. was added slowly a solution of oxalylchloride (61.0 mL, 0.700 mmol) in dichloromethane (20 mL). The reactionwas stirred for 10 minutes at 0° C., then at ambient temperature for 4hours. The solution was concentrated under reduced pressure, then wasconcentrated from dichloromethane twice. The residue was dissolved indichloromethane (15 mL) and added dropwise to a flask containingconcentrated ammonium hydroxide (250 mL) cooled in an ice bath. Thereaction was stirred at ambient temperature overnight. The mixture wasextracted with dichloromethane (600 mL, then 2×100 mL). The organiclayers were combined, washed with water and brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to yield abrown solid that was purified by trituration with diethyl ether/hexanes.A tan solid was isolated by filtration to provide 30.98 g of5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carboxamide. ¹H-NMR (300 MHz,CDCl₃) δ 6.70 (br s, 1H), 6.59 (s, 1H), 5.32 (br s, 1H), 3.99 (t, J=7.3Hz, 2H), 3.61-3.54 (m, 2H), 2.69-2.59 (m, 2H), 1.94-1.76 (m, 6H), 0.94(t, J=7.4 Hz, 3H).

Part D

5-(4-Chlorobutyl)-1-propyl-1H-pyrazole-3-carboxamide (30.95 g, 0.127mmol) in toluene (250 mL) was treated with phosphorous oxychloride(24.86 mL, 0.267 mol). The solution was heated at reflux for 40 minutes.The reaction was worked-up as described in Part D of Examples 37-39,with the exception that chloroform was used in place of methyltert-butyl ether, to yield 5.20 g of5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile as an oil. ¹H-NMR(300 MHz, CDCl₃) δ 6.43 (s, 1H), 4.04( t, J=7.3 Hz,2H),3.62-3.53 (m,2H), 2.70-2.58 (m, 2H), 1.94-1.76 (m, 6H), 0.93 (t, J=7.4 Hz, 3H).

Part E

5-(4-Chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile (14.00 g, 62.0mmol) was converted into4-bromo-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile accordingthe procedure described in Part F of Examples 1-4. Chloroform was usedinstead of dichloromethane in the extraction step during the work-up.The crude product was purified by chromatography on a HORIZON HPFCsystem (silica gel, gradient elution with 10-25% ethyl acetate inhexanes) to provide 14.80 g of4-bromo-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile as ayellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 4.07 (t, J=7.3 Hz, 2H), 3.59 (t,J=6.1 Hz, 2H), 2.79-2.69 (m, 2H), 1.96-1.69 (m, 0.95 (t, J=7.4 Hz, 3H).

Part F

To a mixture of4-bromo-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile (8.25 g,27.1 mmol) and powdered molecular sieves (1 g) in toluene (170 mL) wasadded 2-aminophenylboronic acid hydrochloride (9.40 g, 54.2 mmol),potassium phosphate (28.62 g, 135 mmol),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.701 g,0.677 mmol) and bis(2-diphenylphosphinophenyl)ether (0.437 g, 0.812mmol). Nitrogen gas was bubbled through the mixture for 5 minutes. Themixture was heated at 110° C. for 22 hours. After cooling to ambienttemperature, the mixture was filtered through a plug of CELITE filteragent with 3:2 chloroform/methanol. The filtrate was concentrated underreduced pressure to yield a residue that was used in the next step.

Part G

Acetyl chloride (6.38 g, 81.3 mmol) was added to ethanol (20 mL) at 0°C. The resulting solution was added to the residue from Part F. Thesolution was heated at reflux overnight. Upon cooling to ambienttemperature, the solution was concentrated under reduced pressure. Theresidue was partitioned between chloroform and 2 M aqueous sodiumcarbonate. The aqueous layer was extracted twice with chloroform, andthe combined organic layers were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The crude product was purifiedby chromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-30% CMA in chloroform) followed by recrystallization fromacetonitrile to afford 4.31 g of1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine asoff-white crystals, mp 172-173° C.

¹H-NMR (300 MHz, DMSO-d₆) δ 7.93 (dd, J=7.8, 1.1 Hz, 1H), 7.49 (dd,J=8.1, 1.2 Hz, 1H), 7.36-7.27 (m, 1H), 7.24-7.15 (m, 1H), 6.62 (br s,2H), 4.35 (t, J=7.2 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H), 3.31-3.23 (m, 2H),2.01-1.86 (m, 4H), 1.84-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H);

¹³C-NMR (75 MHz, DMSO-d₆) δ 150.5, 143.7, 137.3, 135.5, 125.60, 125.55,121.7, 121.5, 119.5, 116.3, 50.7, 44.9, 31.3, 25.7, 23.9, 23.5, 10.9;

MS (APCI) m/z 317.1 (M+H)⁺;

Anal. calcd for C₁₇H₂₁ClN₄: C, 64.45; H, 6.68; N, 17.68. Found: C,64.44; H, 6.88; N, 17.79.

Example 471-(2-Methylpropyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A solution of1-(2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.8 g, 3mmol), prepared as described in Example 1, in trifluoroacetic acid (10mL) was treated with platinum (IV) oxide (0.5 g) and shaken underhydrogen pressure (50 psi, 3.4×10⁵ Pa) for 24 hours on a Parr apparatus.The reaction mixture was diluted with chloroform (20 mL) and methanol(10 mL) and filtered through a layer of CELITE filter agent. Thefiltrate was concentrated under reduced pressure. The residue wassuspended in 6 M aqueous hydrochloric acid (5 mL), stirred for 30minutes, and treated with 50% aqueous sodium hydroxide to adjust themixture to pH 13. A precipitate formed and was isolated by filtration,washed with water, and dried. The crude product was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-35% CMA in chloroform) to yield 0.55 g of1-(2-methylpropyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas an off-white powder, mp 167-168° C.

¹H-NMR (300 MHz, CDCl₃) δ 5.02 (br s, 2H), 4.264.16 (m, 2H), 2.94-2.83(m, 4H), 2.79-2.69 (m, 2H), 2.05-1.92 (m, 3H), 1.89-1.76 (m, 4H), 0.97(d, J=6.7 H) 0.95 (t, J=7.5 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 148.3,141.2, 135.3, 134.9, 123.1, 112.1, 51.9, 34.2, 32.0, 30.7, 25.5, 23.9,23.3, 23.0, 22.3, 11.2;

MS (APCI) m/z 287.2 (M+H)⁺;

Anal. calcd for C₁₇H₂₆N₄.0.01CF₃COOH: C, 71.09; H, 9.12; N, 19.48; F,0.20. Found: C, 70.77; H, 9.37; N, 19.27; F, 0.22.

Example 482-Ethyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

2-Ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.700 g,1.61 mmol), prepared as described in Example 2, was reduced using theprocedure described in Example 47. After chromatographic purification,the product was crystallized from acetonitrile to yield 0.39 g of2-ethyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white crystalline solid, mp 206-207° C.

¹H-NMR (300 MHz, CDCl₃) δ 14.58 (br s, 1H), 10.88 (br s, 1H), 6.21 (brs, 1H), 4.33 (q, J=7.3 Hz, 2H), 2.88 (d, J=7.6 Hz, 2H), 2.86-2.71 (m,4H), 1.95 (heptet, J=6.9 Hz, 1H), 1.88-1.76 (m, 4H), 1.56 (t, J =7.3 Hz,3H), 0.99 (d, J =6.7 Hz, 6H);

¹³C-NMR (75 MHz, CDCl3) δ 149.2, 137.0, 133.2, 131.6, 122.7, 112.2,45.9, 33.9, 30.5, 26.5, 24.4, 22.3, 22.0, 21.6, 15.4;

MS (APCI) m/z 273.2 (M+H)⁺;

Anal. calcd for C₁₆H₂₄N₄.1.02CF₃COOH: C, 55.74; H, 6.49; N, 14.41; F,14.96. Found: C, 55.41; H, 6.90; N, 14.38; F, 14.68.

Example 491-(2-Cyclohexylethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

2-Methyl-1-(2-phenylethyl)-2H-pyrazolo[3 ,4-c]quinolin-4-amine (0.79 g,2.6 mmol), prepared as described in Example 40, was reduced using theprocedure described in Example 47. After chromatographic purification,the product was crystallized from acetonitrile to yield 0.44 g of1-(2-cyclohexylethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 230-231° C.

¹H-NMR (300 MHz, CDCl₃) δ 4.96 (br s, 2H), 4.02 (s, 3H), 3.03-2.93 (m,2H), 2.91-2.81 (m, 2H), 2.78-2.68 (m, 2H), 1.91-1.61 (m, 9H), 1.54-1.10(m, 6H), 1.08-0.89 (m, 2H);

¹³C-NMR (75 MHz, CDCl₃) δ 148.0, 141.3, 136.4, 135.2, 122.8, 112.0,38.2, 37.8, 37.3, 33.1, 31.9, 26.5, 26.2, 25.1, 23.3, 22.9;

MS (APCI) m/z 313.2 (M+H)⁺;

Anal. calcd for C₁₉H₂₈N₄.0.12 H₂O: C, 72.53; H, 9.05; N, 17.81. Found:C, 72.27; H, 9.16; N, 17.41.

Example 501-(2-Aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A modification of the method described in Part A of Example 11 wasfollowed. A mixture of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodiumsalt (prepared as described in Part A of Example 23, 100 g, 295 mmol) inglacial acetic acid (0.3 L) was cooled to 9° C. before the addition ofmethylhydrazine (16.0 mL,300 mmol). During the addition, the reactiontemperature did not exceed 16° C. Solids were rinsed from the inside ofthe flask walls into the mixture with acetic acid (50 mL) and themixture was allowed to warm to ambient temperature and stir overnight.Water was added to the mixture and additional solid precipitated. Thesolid was isolated by filtration, dried, and recrystallized fromethanol. The solid was isolated and dried to yield 75.2 g of ethyl5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate.

Part B

A solution of ethyl5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate(75.2 g, 230 mmol) in 1 M aqueous hydrochloric acid (450 mL) and aceticacid (450 mL) was heated at 100° C. (internal temperature) for 5.2hours, cooled to ambient temperature, and stirred for about 12 hours. Awhite solid was isolated by filtration, washed with water, and dried toprovide 52.6 g of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylicacid.

Part C

Toluene (250 mL) and thionyl chloride (30.4 mL, 418 mmol) were added to5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylicacid (50.0 g, 167 mmol). The mixture was heated at reflux for 2 hours,cooled to ambient temperature, and poured onto ice. A solid was isolatedby filtration, washed with water, and dried to afford 47.5 g of a whitesolid.

Part D

To a solid from Part C (25.0 g) in dichloromethane (250 mL) at 0° C. wasadded concentrated ammonium hydroxide (50 mL) in one portion. Themixture was stirred for 5 minutes, then hexanes (200 mL) was added andthe mixture was filtered, washed with water, then dried to provide 13.07g of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamideas a white powder.

Part E

To a mixture of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide(10.5 g, 35.2 mmol) and pyridine (5.69 mL, 70.4 mmol) in dichloromethane(200 mL) at 0° C. was added trifluoroacetic anhydride (5.47 mL, 38.7mmol) over two minutes. The solution was stirred at 0° C. for about 20minutes, then was allowed to warm to ambient temperature. After 2 hours,more pyridine (2.8 mL) and trifluoroacetic anhydride (1.5 mL) wereadded. The reaction was quenched by adding 2 M sodium carbonate (200mL). The mixture was extracted with chloroform. The organic layers werecombined, dried over magnesium sulfate, filtered, and concentrated underreduced pressure to a volume of about 50 mL. A white solid was present.Heptane (150 mL) was added, and the mixture was concentrated to a volumeof about 25 mL, then hexanes were added and the solid was collected byfiltration. The white solid was washed with hexanes and dried to provide8.50 g of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrilethat contained a small amount of an impurity.

Part F

To a mixture of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile(8.50 g, 30.3 mmol) and potassium acetate (4.50 g, 45.5 mmol) in aceticacid (40 mL) and dichloromethane (120 mL) was slowly added bromine (6.79g, 42.5 mmol). The mixture was stirred overnight. Saturated aqueoussodium hydrogensulfite was added until the mixture became colorless,then the mixture was concentrated under reduced pressure to form aslurry. Water (200 mL) was added to the slurry and a white solid wasisolated by filtration, washed with water, and dried to afford 9.15 g of4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrileas a white solid.

Part G

A mixture of hydrazine hydrate (6.40 g, 127 mmol) and4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile(9.15 g, 25.5 mmol) in ethanol (200 mL) was heated at reflux for 80minutes, then was allowed to cool to ambient temperature in a waterbath. A precipitate formed and was isolated by filtration and washedwith cold ethanol. The filtrate was concentrated under reduced pressure,and the resulting white solid was twice treated with toluene andconcentrated under reduced pressure then dried under vacuum to provide5.74 g of 5-(2-aminoethyl)-4-bromo-1-methyl-1H-pyrazole-3-carbonitrileas an off-white solid.

Part H

Di-tert-butyl dicarbonate (13.3 g, 60.9 mmol) was added to a mixture of5-(2-aminoethyl)-4-bromo-1-methyl-1H-pyrazole-3-carbonitrile (11.62 g,50.7 mmol) in 1-methyl-2-pyrrolidinone at 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 20 minutes; asolution formed. Water was added to the stirred solution, causing asolid to form. The mixture was cooled and the solid was isolated byfiltration, washed with water, and dried. The crude product was purifiedby chromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 60-75% ethyl acetate in hexanes). The appropriate fractions werecombined and concentrated under reduced pressure to provide 12.0 g oftert-butyl 2-(4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)ethylcarbamate asa white solid.

Part I

A mixture of tert-butyl2-(4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)ethylcarbamate (19.1 g, 58.0mmol), 2-aminophenylboronic acid hydrochloride (15.09 g, 87.03 mmol),triphenylphosphine (1.37 g, 5.22 mmol), palladium (II) acetate (390 mg,1.74 mmol), 2 M aqueous sodium carbonate (87 mL, 174 mmol), 1-propanol(100 mL), and water (20 mL) was heated at 100° C. for 4 hours under anitrogen atmosphere. Additional 1-propanol (100 mL) and water (20 mL)were added and the mixture was heated at 100° C. overnight. The mixturewas allowed to cool to ambient temperature and chloroform (200 mL) wasadded. After 10 minutes, the mixture was transferred to a separatoryfunnel and the organic layer was isolated and washed with water (200 mL)and brine (200 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated to provide an oil that was purifiedby flash chromatography (silica gel, eluting sequentially withchloroform, 10% CMA in chloroform, and finally 40% CMA in chloroform) toyield an oil that was used in the next step.

Part J

Acetyl chloride (7.8 g, 100 mmol) was added to ethanol (100 mL) at 0° C.The resulting solution was added to the oil from Part I. The solutionwas heated at reflux overnight. Upon cooling to ambient temperature, aprecipitate formed that was isolated by filtration, washed with a smallamount of cold ethanol, and dried under vacuum at 75° C. for 4 hours togive 7.34 g of1-(2-aminoethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride as a white solid.

Part K

A solution of1-(2-aminoethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride (7.20 g, 22.9 mmol) in trifluoroacetic acid (75 mL) wastreated with platinum (IV) oxide (7.0 g) and shaken under hydrogenpressure (50 psi, 3.4×10⁵ Pa) for 24 hours on a Parr apparatus. Thereaction mixture was diluted with chloroform (50 mL) and methanol (25mL) and filtered through a layer of CELITE filter agent. The filtratewas concentrated under reduced pressure. The residue was suspended inconcentrated hydrochloric acid (5 mL), stirred for 2 hours, treated with50% aqueous sodium hydroxide to adjust the pH to 13, and stirred atambient temperature overnight. The mixture was diluted with water (100mL) and was extracted with chloroform (5×150 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure to yield 5.10 g of1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas an off-white foam.

¹H-NMR (300 MHz, DMSO-d₆) δ 6.12-3.20 (br abs., 4H), 4.04 (s, 3H),3.21-3.10 (m, 2H), 2.91-2.76 (m, 4H), 2.61-2.52 (m, 2H), 1.80-1.67 (m,4H);

MS (APCI) m/z 246.3 (M+H)⁺.

Example 511-(2-Aminoethyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A modification of the method described in Part A of Example 11 wasfollowed. A mixture of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodiumsalt (prepared as described in Part A of example 23, 67.9 g, 200 mmol)in glacial acetic acid (0.2 L) was cooled to 9° C. before the additionof propylhydrazine oxalate (32.8 g, 200 mmol). During the addition, thereaction temperature did not exceed 17° C. The mixture was allowed towarm to ambient temperature and stir for 4 hours. Water (600 mL) wasadded to the mixture and additional solid precipitated. The solid wasisolated by filtration, washed with water, and dried to yield 67.4 g ofa yellow solid. The solid was stirred in 1 M aqueous potassium acetate(311 mL), isolated by filtration, washed with water, dried, andrecrystallized from ethanol/heptane. The final solid was isolated,washed with 2:1 heptane/ethyl acetate, and dried to yield 45.2 g ofethyl5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylate.

Part B

A stirred solution of ethyl5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylate(45.1 g, 127 mmol) in 1 M aqueous hydrochloric acid (157 mL) and aceticacid (157 mL) was heated at 95° C. (internal temperature) for 10 hoursand then cooled to 10° C. Water (300 mL) was added and a white solid wasisolated by filtration, washed with water and diethyl ether, and dried.The solid was treated with toluene (150 mL) and heated at reflux for 3hours with a Dean-Stark trap. The mixture was cooled in an ice bath to10° C. and a solid was isolated by filtration and dried to provide 28.85g of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylicacid.

Part C

Toluene (70 mL) and thionyl chloride (70 mL) were added to5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylicacid (28.8 g, 87.8 mmol) and the mixture was heated at reflux for 1hour, cooled to ambient temperature, and concentrated under reducedpressure to yield a yellow solid. The solid was dissolved indichloromethane (200 mL). The solution was cooled to 0° C., thenconcentrated ammonium hydroxide (125 mL) was added in one portion. Theresulting mixture was stirred for 1 hour at 0° C. The dichloromethanewas removed under reduced pressure. A solid was isolated by filtration,washed with water, and dried to afford 28.70 g of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxamide.

Part D

To a mixture of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxamide(16.3 g, 50.0 mmol) and pyridine (20.9 mL, 150 mmol) in dichloromethane(100 mL) at 0° C. was added a solution of trifluoroacetic anhydride(9.89 mL, 70.0 mmol) in dichloromethane (100 mL) over ten minutes. Thesolution was stirred at 0° C. for about 15 minutes, then was allowed towarm to ambient temperature. After 45 minutes, saturated aqueous sodiumbicarbonate (200 mL) was added and the dichloromethane was removed underreduced pressure. A white solid was isolated by filtration, washed withwater, and dried. The solid was recrystallized from 1:1 heptane/ethylacetate to yield5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile.

Part E

To a solution of5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile(14.1 g, 45.7 mmol) and potassium acetate (6.73 g, 68.6 mmol) in aceticacid (91 mL) and dichloromethane (46 mL) was slowly added bromine (3.28g, 64.0 mmol). The mixture was stirred for one day. Saturated aqueoussodium hydrogensulfite was added until the mixture became colorless,then the mixture was concentrated under reduced pressure to form aslurry. Water (450 mL) was added to the slurry and a white solid wasisolated by filtration, washed with water, and dried to afford 17.24 gof4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrileas a white solid.

Part F

A mixture of hydrazine hydrate (11.1 g, 222 mmol) and4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carbonitrile(17.2 g, 44.4 mmol) in ethanol (570 mL) was heated at reflux for 90minutes, then was allowed to cool to ambient temperature. A precipitatewas isolated by filtration and washed with cold ethanol. The filtratewas concentrated under reduced pressure to generate an off-white solidthat was suspended in dichloromethane (133 mL). Di-tert-butyldicarbonate (11.6 g, 53.3 mmol) was added to the mixture, which was thenstirred overnight. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to yield a yellow oil. The crudeproduct was purified by chromatography on a HORIZON HPFC system (silicagel, gradient elution with 40-60% ethyl acetate in hexanes). Theappropriate fractions were combined and concentrated under reducedpressure to provide 15.8 g of tert-butyl2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)ethylcarbamate as acolorless oil.

Part G

A flask containing a mixture of tert-butyl2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)ethylcarbamate (15.8 g, 44.2mmol), 2-aminophenylboronic acid hydrochloride (11.5 g, 66.3 mmol),triphenylphosphine (1.04 g, 3.98 mmol), palladium (II) acetate (299 mg,1.33 mmol), 2 M aqueous sodium carbonate (67 mL, 133 mmol), 1-propanol(77.4 mL), and water (15.5 mL) was heated overnight under a nitrogenatmosphere in a 100° C. oil bath. The reaction was allowed to cool toambient temperature and water (300 mL) was added. The mixture wasextracted with chloroform, dried over magnesium sulfate, filtered, andconcentrated to provide an oil that was purified twice by flashchromatography (silica gel, first column: eluted sequentially with 0-10%CMA in chloroform, and then 25% CMA in chloroform; second column:gradient elution with 50-60% ethyl acetate in hexanes) to yield 7.3 g oftert-butyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate as ayellow resin.

Part H

Acetyl chloride (7.1 mL, 100 mmol) was added to ethanol (100 mL) at 0°C. The resulting solution was added to the tert-butyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate fromPart G. The solution was heated at reflux for 9.5 hours. Upon cooling toambient temperature, a precipitate formed that was isolated after twodays by filtration, washed with a small amount of cold ethanol, anddried to yield 5.78 g of1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride as a white solid.

Part I

1-(2-Aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride (2.50 g, 7.30 mmol) was reduced using the proceduredescribed in Example 47. After the reaction was filtered andconcentrated, the residue was triturated with diethyl ether toprecipitate a solid that was isolated by filtration, washed with diethylether, and dried under vacuum. After chromatographic purification, theproduct was crystallized from acetonitrile to yield 0.44 g of thebis-trifluoroacetic acid salt of1-(2-aminoethyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, 228-230° C.

¹H-NMR (300 MHz, DMSO-d₆) δ 13.13 (s, 1H), 9.30-6.50 (br peaks, 5H),4.42 (t, J=7.2 Hz, 2H), 3.47-3.33 (m, 2H), 3.11-2.92 (m, 2H), 2.87-2.75(m, 2H), 2.68-2.57 (m, 2H), 1.99-1.86 (m, 2H) 1.86-1.68 (m, 4H);

MS (APCI) m/z 274.3 (M+H)⁺.

Examples 52-55

A mixture of tert-butyl N-(2-pyridyl)carbamate (prepared as described inPart A of Example 15, 1.9 equivalents) in l-propanol (15 mL) and 1 Maqueous HCl (15 mL) was heated at 80° C. for 1 hour. The reaction wasallowed to cool to ambient temperature and solid sodium carbonate (1.5equivalents) was added with stirring. A solution of a4-bromo-1,5-disubstitued-1H-pyrazole-3-carbonitrile (1.51-2.07 g,6.63-7.80 mmol, 1 equivalent) shown in the table below in 1-propanol(4-5 mL) was added, followed by triphenylphosphine (0.06 equivalent) andpalladium (H) acetate (0.02 equivalent). In Example 55,tetrakis(triphenylphosphine)palladium(0) (0.05 equivalent) was usedinstead of triphenylphosphine and palladium (II) acetate. The flask wasfitted with a reflux condenser and a nitrogen inlet line, then wasplaced under vacuum and back-filled with nitrogen three times. The paleyellow solution was heated under a nitrogen atmosphere at 100° C. for18-21 hours. The 1-propanol was evaporated under reduced pressure. Theremaining liquid was dissolved in chloroform (100 mL), washed with water(100 mL), dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution using 0-30% CMA inchloroform). In Example 55, a gradient elution with 0-25% CMA inchloroform was used. The appropriate fractions were combined andconcentrated to yield a pale yellow solid that was recrystallized fromboiling acetonitrile. White crystals were isolated, washed with coldacetonitrile, and dried overnight at 60° C. in a vacuum oven to providethe product.

Example 52: Isolated 0.18 g of1,2-diethyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amine as off-whiteneedles, mp 286-288° C.

¹H NMR (300 MHz, d₆-DMSO) δ 8.46 (dd, J=4.7, 1.9, 1H), 8.24 (dd, J=7.8,1.9, 1H), 7.16 (dd, J=7.8, 4.7, 1H), 7.05 (s, 2H), 4.42 (q, J=7.1, 2H),3.24 (q, J=7.5, 2H), 1.47 (t, J=7.1, 3H), 1.24 (t, J=7.5, 3H);

¹³C NMR (75 MHz, d₆-DMSO) δ 154.6, 153.0, 146.9, 139.8, 135.2, 129.8,117.0, 115.8, 114.2,44.5, 18.2, 15.9, 13.1;

Anal. calcd for C₁₃H₁₅N₅: C, 64.71; H, 6.27; N, 29.02. Found: C, 64.49;H, 6.31; N, 29.19.

Example 53: Isolated 90 mg of1-ethyl-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amine asoff-white needles, mp 303-305° C.

¹H NMR (300 MHz, d₆-DMSO) δ 8.46 (dd, J=4.7, 1.9, 1H), 8.24 (dd, J =7.8,1.9, 1H), 7.16 (dd, J=7.8, 4.7, 1H), 7.06 (s, 2H), 4.34 (q, J=6.9, 2H),3.24 (q, J=7.5, 2H), 1.90 (sextet, J=7.1, 2H), 1.26 (t, J=7.8, 3H), 0.91(t, J=7.5, 3H);

¹³C NMR (75 MHz, d₆-DMSO) δ 153.0, 149.5, 146.9, 140.3, 135.2, 129.8,117.0, 115.7, 114.2, 50.9, 23.6, 18.2, 13.1, 10.9;

Anal. calcd for C₁₄H₁₇N₅: C, 65.86; H, 6.71; N, 27.43. Found: C, 65.80;H, 6.67; N, 27.50.

Example 54: Isolated 0.156 g of2-methyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amineas off-white needles, mp 323-326° C.

¹H NMR (300 MHz, d₆-DMSO) δ 8.49 (dd, J=7.9, 1.9, 1H), 8.44 (dd, J =4.6,1.6, 1H), 7.12 (dd, J=7.8, 4.7, 1H), 7.08 (s, 2H), 4.10 (s, 3H), 3.23(s, 2H), 0.99 (s, 9H);

¹³C NMR (75 MHz, d₆-DMSO) δ 154.8, 153.0, 147.0, 137.5, 135.0, 130.5,117.5, 116.4, 114.4, 38.4, 37.0, 35.3, 29.4;

Anal. calcd for C₁₅H₁₉N₅: C, 66.89; H, 17.11; N, 26.00. Found: C, 66.95;H, 6.95; N, 26.08.

Example 55: Isolated 0.24 g of2-benzyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amineas off-white needles, mp 232-235° C.

¹H NMR (300 MHz, d₆-DMSO) δ 8.46 (dd, J=4.4, 1.6, 1H), 8.28 (dd, J =7.8,1.9, 1H), 7.36-7.27 (m, 3H), 7.19-7.13 (m, 5H), 5.70 (s, 2H), 3.12 (d,J=8.5, 2H), 1.95 (septet, J=6.9, 1H), 0.92 (d, J=6.6, 6H);

¹³C NMR (75 MHz, d₆-DMSO) δ 154.8, 153.1, 147.1, 138.9, 136.9, 135.6,130.2, 128.6, 126.7, 116.9, 114.1, 53.3, 33.2, 28.6, 21.8;

Anal calcd for C₂₀H₂₁N₅: C, 72.48; H, 6.39; N, 21.13. Found: C, 72.24;H, 6.56; N, 21.18.

Examples 52-55

EXAMPLES 52-55

Example Starting Material R₁ R₂ 524-Bromo-1,5-diethyl-1H-pyrazole-3-carbonitrile —CH₂CH₃ —CH₂CH₃ (preparedExample 11) 53 4-Bromo-5-ethyl-1-propyl-1H-pyrazole-3- —CH₂CH₃—CH₂CH₂CH₃ carbonitrile (prepared in Example 44) 544-Bromo-1-methyl-5-(2,2-dimethylpropyl)-1H- —CH₂C(CH₃)₃ —CH₃pyrazole-3-carbonitrile (prepared in Example 37) 554-Bromo-1-benzyl-5-(2-methylpropyl)-1H- —CH₂CH(CH₃)₂ —CH₂C₆H₅pyrazole-3-carbonitrile (prepared in Example 8)

Example 562-Butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-amine

Part A

A 2.5 M solution of n-butyl lithium in hexane (100 mL, 250 mmol) wasadded over 20 minutes to a stirred solution of tert-butylpyridin-4-ylcarbamate (19.4 g, 100 mmol) andN,N,N′,N′-tetramethylethylenediamine (31.4 g, 270 mmol) in THF (500 mL)at −78° C. tert-Butyl pyridin-4-ylcarbamate is available from aliterature procedure (Spivey, A. C. et al. J. Org. Chem. 1999, 64,9430-9443). A white solid appeared and the mixture was stirred for 10minutes at −78° C., then was allowed to warm slowly to −4° C. beforecooling to −78° C. again. Trimethyl borate (39.5 g, 380 mmol) was addedover 15 minutes. The solution was allowed to warm to 0° C., then waspoured into saturated aqueous ammonium chloride (500 mL). The mixturewas stirred for 2 minutes. After standing at ambient temperatureovernight, the mixture was partitioned between diethyl ether and brine.The organic layer was separated and washed with brine. A white solidformed in the organic layer and was isolated by filtration. The solidwas washed sequentially with diethyl ether, water, and diethyl ether,then was dried to provide 17.1 g of4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronic acid as a white solid.

Part B

2-Butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-aminewas synthesized from 4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronicacid (2.48 g, 10.4 mmol) and4-bromo-1-butyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (preparedas described in Parts A-F of Example 4, 1.56 g, 5.49 mmol) according tothe reaction conditions described in Examples 52-54. Additionalpalladium (II) acetate (50 mg) and triphenylphosphine (170 mg) wereadded after the reaction had been heated for 23 hours. After theaddition, the flask was placed under vacuum and back-filled withnitrogen twice. The solution was heated at 100° C. for an additional 29hours. The reaction was worked-up and purified as described in Example54, but was not recrystallized from acetonitrile, to provide 25 mg of2-butyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]-1,6-naphthyridin-4-amineas an off-white solid.

¹H NMR (300 MHz, d₆-DMSO) δ 9.10 (s, 1H), 8.31 (d, J =5.4, 1H), 7.30 (d,J=5.4, 1H), 7.25 (s,2H), 4.37 (t, J=7.2, 2H), 3.17 (d, J=7.5, 2H),2.10-1.86 (m, 3H), 1.39-1.32 (m, 2H), 0.99 (d, J=6.6, 6H), 0.92 (t,J=7.6, 3H);

HRMS Measured Mass (M+H)⁺ 298.2023.

Example 572-Propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A mixture of1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 46, 5.00 g, 15.8 mmol), 4-dimethylaminopyridine(0.04 g, 0.316 mmol), di-tert-butyldicarbonate (13.8 g, 63.12 mmol), andtriethylamine (5.50 mL, 39.5 mmol) was heated at 90° C. for 20 minutesand a solution formed. The temperature was decreased to 60° C. and thesolution was heated for I hour. The solution was allowed to cool toambient temperature and was concentrated under reduced pressure. Theresulting oil was partitioned between dichloromethane and 1 M aqueouspotassium hydroxide. The organic layer was washed with water and brine,dried over sodium sulfate, filtered, and concentrated to a yield an oilthat was dried under vacuum. The oil was triturated with anapproximately 1:1 diethyl ether/hexanes solution, resulting in theformation of a solid that was isolated by filtration and dried toprovide 5.68 g of di(tert-butyl)1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a tan solid.

Part B

Potassium acetate (0.83 g, 8.432 mmol) and sodium iodide (16 g, 1.05mmol) was added to a solution of di(tert-butyl)1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(2.18 g, 4.22 mmol) in DMF (15 mL). The reaction mixture was heated at90° C. under a nitrogen atmosphere for 4.5 hours. The reaction wasallowed to cool to ambient temperature and the volatiles were removedunder reduced pressre. The resulting oil was partitioned between ethylacetate and water. The organic layer was isolated and washed with water(2×25 mL) and brine (3×20 mL), dried over magnesium sulfate, filtered,and concentrated under reduced pressure to yield an oil that was driedunder vacuum to provide 1.76 g of4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl}butylacetate.

Part C

Potassium carbonate (6 mg, 0.041 mmol) was added to a solution of4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl}butylacetate (0.8823 g, 1.632 mmol) in methanol (5 mL). The mixture wasstirred at ambient temperature for 1.3 hours. The volatiles were removedunder reduced pressure. The resulting oil was purified by flashchromatography (silica gel, eluted with 100% ethyl acetate) to yield0.1466 g of di(tert-butyl)1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonatein about 87% purity.

Part D

To dichloromethane (5 mL) at −78° C. was added dimethylsulfoxide (0.12mL, 1.6 mmol) and oxalyl chloride (0.11 mL, 1.2 mmol). After severalminutes, a solution di(tert-butyl)1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(0.5449 g, 1.093 mmol) and triethylamine (0.46 mL, 3.3 mmol) indichloromethane (5 mL) was added dropwise to the −78° C. solution. After15 minutes, the cooling bath was removed and the solution was allowed towarm to ambient temperature, during which time more dichloromethane (20mL) was added. The solution was transferred to a separatory funnel andwashed with aqueous potassium carbonate, water, and brine. The solutionwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting oil was dried under vacuum to yield 0.5845 g ofdi(tert-butyl)1-(4-oxobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonatethat contained a small amount of dimethylsulfoxide, but was used withoutfurther purification.

Part E

Diethyl 1-diazo-2-oxopropylphosphonate (0.28 g, 1.3 mmol) was preparedby the method of Bestmann, H. J. et al., Synlett, 1996, 6, 521-522 andadded to a stirred mixture of di(tert-butyl)1-(4-oxobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(0.543 g, 1.09 mmol) and potassium carbonate (0.31 g, 2.2 mmol) inmethanol (5 mL) at ambient temperature. After 4 hours, the reaction wasconcentrated under reduced pressure. The oil was dissolved indichloromethane, washed with water and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by flash chromatography (silica gel, eluted with 5% ethylacetate in dichloromethane) to yield 0.2498 g of a white solid that wasused without further purification in the next step.

Part F

N-Chlorosuccinimide (0.15 g, 1.0 mmol) was added to a solution of3-pyridine aldoxime (0.13 g, 1.0 mmol ) in THF (5 mL). The solution wasstirred at ambient temperature for 1 day. The material from Part E(0.2498 g, 0.5071 mmol) and anhydrous triethylamine (0.16 mL, 1.1 mmol)were added and the solution was heated at 60° C. for 20 hours. Thevolatiles were removed under reduced pressure to yield a brown oil thatwas purified by flash chromatography (silica gel, sequential elutionwith 40% ethyl acetate in hexanes, 40% ethyl acetate in dichloromethane,and finally 100% ethyl acetate) to yield 0.1105 g of material that wasused without further purification in the next step.

Part G

A solution of the material from Part F (0.1105 g) in a solution of 1:1ethanol/concentrated hydrochloric acid was heated at 60° C. under anitrogen atmosphere for 2 hours. The volatiles were removed underreduced pressure. The resulting oil was dissolved in water and 1 drop of50% aqueous sodium hydroxide was added to adjust the pH to 14. Themixture was extracted with dichloromethane several times. The organiclayers were combined, washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to yield anoil. The oil was dried under vacuum, then triturated with hexanes toyield a solid that was isolated by filtration. The solid was dried undervacuum at 70° C. to yield 0.0376 g of2-propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 192.0-193.0° C.

¹H NMR (300 MHz, CDCl₃) δ 8.99 (dm, J=1.5 Hz, 1H), 8.68 (dm, J=3.2 Hz,1H), 8.11 (dm, J=8.0 Hz, 1H), 7.81(d, J=6.7 Hz, 1H), 7.70 (d, J =7.1 Hz,1H), 7.40-7.43 (m, 2H), 7.23-7.28 (m, 1H), 6.38 (s, 1H), 5.36 (s, 2H),4.29 (t, J =7.4 Hz, 2H), 3.47 (t, J=7.9 Hz, 2H), 3.03 (t, J=7.3 Hz, 2H),2.26 (t, J=7.9 Hz, 2H), 1.98 (q, J=7.3 Hz, 0.99 (t, J=7.4 Hz, 3H);

MS (APCI) m/z 412 (M+H)⁺;

Anal. calcd for C₂₄H₂₄N₆O.0.2C₂H₆O: C, 69.50; H, 6.02; N, 19.93. Found:C, 69.15; H, 5.75; N, 20.09.

Example 581-(2-Cyclohexylethyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A mixture of2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 41, 575 mg, 1.81 mmol) and platinum (IV) oxide(290 mg) in trifluoroacetic acid (8 mL) was shaken under hydrogenpressure (50 psi, 3.4×10⁵ Pa) for 22.5 hours on a Parr apparatus. Thereaction mixture was filtered through a poly(tetrafluoroethylene)membrane to remove the catalyst. The filtrate was concentrated underreduced pressure. The crude product was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution using 0-30% CMA inchloroform) and the appropriate fractions were concentrated to yield asolid that was slurried in hot acetonitrile. The mixture was allowed tocool to ambient temperature with stirring, then 318 mg of1-(2-cyclohexylethyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-aminewas isolated as a white powder, mp 177.0-179.0° C.

MS (APCI) m/z 327 (M+H)⁺;

Anal. calcd for C₂₀H₃₀N₄: C, 73.58; H, 9.26; N, 17.16. Found: C, 73.48;H, 9.01; N, 17.16.

Example 591-(2-Cyclohexylethyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A mixture of1-(2-phenylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 42, 400 mg, 1.21 mmol) and platinum (IV) oxide(200 mg) in trifluoroacetic acid (8 mL) was shaken under hydrogenpressure (50 psi, 3.4×10⁵ Pa) on a Parr apparatus for 18 hours andworked up using the method described in Example 58 to afford 217 mg of1-(2-cyclohexylethyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 173-174.5° C.

MS (APCI) m/z 341 (M+H)⁺;

Anal. calcd for C₂₁H₃₂N₄: C, 74.07; H, 9.47; N, 16.45. Found: C, 73.77;H, 9.73; N, 16.49.

Example 602-Butyl-1-[2-(propylsulfonyl)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Solid sodium hydride (60% dispersion in oil, 2.90 g, 72.3 mmol) wasadded in portions over 5 minutes to a stirred solution of 1-propanethiol(6.00 g, 78.8 mmol) in tetrahydrofuran (262 mL). After 15 minutes, athick white suspension had formed. To the suspension was added1-chloro-3-butanone (7.00 g, 65.7 mmol), which caused the reactionmixture to warm and a cloudy solution to form. After 30 minutes, thecloudy solution was partitioned between ethyl acetate (100 mL) and water(100 mL). The layers were separated and the organic layer was washedwith saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford a pale brown oil. The crude product was purified byflash chromatography (silica gel, elution with 20% ethyl acetate inhexanes) to provide 9.0 g of 4-(propylthio)butan-2-one as a clearliquid.

Part B

A neat mixture of 4-(propylthio)butan-2-one (9.00 g, 61.5 mmol) anddiethyl oxalate (9.00 g, 61.5 mmol) was added dropwise to a stirredsolution of sodium tert-butoxide (5.90 g, 61.5 mmol) in ethanol (44 mL)at ambient temperature. Following the addition, the reaction was stirredfor two hours. Acetic acid (35 mL) was added, followed by potassiumacetate (7.24 g, 73.8 mmol). The mixture was cooled in a cold waterbath. Butylhydrazine (11.0 g, 61.5 mmol) was added in portions. After 15minutes, the mixture was allowed to warm to ambient temperature and wasstirred for 2 hours. The volatiles were removed under reduced pressureto yield an oil. Saturated aqueous sodium carbonate was added to the oiluntil a pH of 10 was reached. The mixture was extracted withdichloromethane (3×50 mL). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The orange oil was purified by flash chromatography(silica gel, elution with 20% ethyl acetate in hexanes) to provide 10.6g of ethyl 1-butyl-5-[2-(propylthio)ethyl]-1H-pyrazole-3-carboxylate asan orange oil.

Part C

To a stirred solution of1-butyl-5-[2-(propylthio)ethyl]-1H-pyrazole-3-carboxylate (10.6 g, 35.5mmol) in chloroform (355 mL) was added mCPBA (20.4 g, 71.0 mmol) inportions over 15 minutes. After 1 hour, the mixture was partitionedbetween chloroform and saturated aqueous sodium carbonate (100 mL). Thelayers were separated and the organic layer was washed with saturatedaqueous sodium carbonate (100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford an oil. The crude product was purified by flashchromatography (silica gel, elution with 20% ethyl acetate in hexanes)to afford 5.65 g of ethyl1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxylate.

Part D

To a solution of ethyl1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxylate (5.00 g,15.1 mmol) in ethanol (76 mL) at ambient temperature was added 6 Maqueous sodium hydroxide (5.0 mL, 30 mmol). The solution was stirred for2 hours, then the volatiles were removed under reduced pressure and theresulting oil was dissolved in water (100 mL). The aqueous solution waswashed with dichloromethane (50 mL) and then the pH was adjusted with 1M hydrochloric acid to pH 4. A precipitate formed and the mixture wasstirred for 1 hour. The solid was isolated by filtration, washed withwater, and dried to provide 4.6 g of1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxylic acid as awhite powder.

Part E

To a solution of1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxylic acid (4.00g, 13.22 mmol) in dichloromethane (66 mL) was added oxalyl chloride (3.5mL, 39.7 mmol) and a drop of DMF. The solution bubbled vigorously andwas stirred at ambient temperature for 30 minutes. The solution wasconcentrated under reduced pressure. The residue was dissolved indichloromethane (66 mL) and the resulting solution was cooled in an icebath, then concentrated ammonium hydroxide (66 mL) was added dropwise.After the addition was complete, the ice bath was removed and themixture was stirred at ambient temperature for 2 hours. The volatileswere removed under reduced pressure to afford a slurry that wasextracted with chloroform (2×100 mL). The organic layers were combinedand concentrated under reduced pressure to afford 4.0 g of1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide as a whitesolid.

Part F

1-Butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide (4.00 g,13.27 mmol) in toluene (66 mL) was treated with phosphorous oxychloride(2.50 mL, 26.5 mol). The solution was heated at reflux for 1 hour. Thereaction mixture was allowed to cool to ambient temperature and thevolatiles were removed under reduced pressure. The resulting oil wasdiluted with water (50 mL) and saturated aqueous sodium bicarbonate. Themixture was extracted with dichloromethane (2×50 mL). The organic layerswere combined, washed with saturated aqueous sodium bicarbonate (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide 3.8 g of1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile as abrown oil.

Part G

Bromine (0.8 mL, 14.7 mmol) was added dropwise to a stirred solution ofpotassium acetate (2.00 g, 20.1 mmol) and1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile ( 3.80 g,13.4 mmol) in acetic acid (27 mL). The reaction was stirred at ambienttemperature, then was concentrated under reduced pressure to afford asolid. Saturated aqueous sodium bicarbonate was added to the solid untilthe mixture was pH 9. The mixture was extracted with dichloromethane(2×50 mL). The organic layers were combined and concentrated underreduced pressure to afford a brown oil. The crude product was purifiedby flash chromatography (silica gel, elution with 40% ethyl acetate inhexanes) to yield 2.85 g of4-bromo-1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrileas a white solid.

Part H

To a mixture of4-bromo-1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile(2.35 g, 6.49 mmol) and powdered molecular sieves (1 g) in toluene (41mL) was added 2-aminophenylboronic acid hydrochloride (2.25 g, 12.97mmol), potassium phosphate (6.90 g, 32.5 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.148 g, 0.162 mmol) andbis(2-diphenylphosphinophenyl)ether (0.105 g, 0. 195 mmol). Nitrogen gaswas bubbled through the mixture for 5 minutes. The mixture was heated at110° C. for 20 hours. After cooling to ambient temperature, the mixturewas filtered through a plug of CELITE filter agent, which was rinseduntil clear with a solution of dichloromethane and methanol. Thefiltrate was concentrated under reduced pressure to yield a residue thatwas used in the next step.

Part I

The material from Part H was dissolved in ethanol (24 mL) and a solutionof hydrogen chloride in ethanol (2.7 M, 7.0 mL, 19 mmol) was added. Thesolution was heated at reflux for 2.5 hours. Upon cooling to ambienttemperature, the solution was concentrated under reduced pressure. Theresulting oil was dissolved in water and the pH was adjusted withsaturated aqueous sodium carbonate to pH 10. The solution was extractedwith dichloromethane (3×50 mL). The organic layers were combined, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by flash chromatography (silica gel,elution with 5% methanol in dichloromethane) to yield an off-white foam(1.50 g) that was crystallized from ethanol (20 mL). The crystals wereisolated by filtration, washed with ethanol, and dried under vacuum at65° C. for 10 hours to yield2-butyl-1-[2-(propylsulfonyl)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amineas tan crystalline plates, mp 169-171° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (d, J=8.1 Hz, 1H), 7.51 (d, J =8.1 Hz,1H), 7.35 (t, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 1H), 6.69 (bs, 2H), 4.42(t, J=7.5 Hz, 2H), 3.70-3.66 (m, 2H), 3.51-3.46 (m, 2H), 3.23-3.18 (m,2H) 1.90 (pentet, J=7.5 Hz, 2H), 1.74 (sextet, J=7.5 Hz, 2H), 1.37(sextet, J=7.5 Hz, 2H), 0.99 (t, J=7.5 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H);

MS (ES1) m/z 375 (M+H)⁺;

Anal. Cacld for C₁₉H₂₆N₄O₂S: C, 60.94; H, 7.00: N, 14.96. Found: C,60.85; H, 6.92; N, 14.90.

Example 612-Butyl-1-[2-(propylsulfonyl)ethyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A solution of2-butyl-1-[2-(propylsulfonyl)ethyl]-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 60, 0.50 g, 1.3 mmol) intrifluoroacetic acid (6 mL) was treated with platinum (IV) oxide (0.5 g)and shaken under hydrogen pressure (50 psi, 3.4×10⁵ Pa) for 20 hours ona Parr apparatus. The reaction mixture was filtered through a layer ofCELITE filter agent, and the CELITE filter agent was rinsed withdichloromethane (100 mL) until the rinses were clear. The filtrate wasconcentrated under reduced pressure. The oil was suspended in water (20mL) and treated with 50% aqueous sodium hydroxide to adjust the mixtureto pH 14, causing a precipitate to form. The mixture was stirred for 1hour, then the precipitate was isolated by filtration and washed withwater. The white powder was recrystallized from acetonitrile (5 mL). Thecrystals were isolated by filtration, washed with acetonitrile, anddried under vacuum at 65° C. to afford 0.40 g of2-butyl-1-[2-(propylsulfonyl)ethyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas white crystals, mp 173-175° C.

¹H NMR (300 MHz, DMSO-d₆) δ 6.02 (bs, 2H), 4.28 (t, J=7.5 Hz, 2H),3.43-3.37 (m, 4H), 3.19-3.14 (m, 2H), 2.85 (bs, 2H) 2.56 (bs, 2H), 1.85(pentet, J=7.5 Hz, 1.77-1.70 (m, 6H), 1.33 (sextet, J=7.5 Hz, 2H), 1.00(t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H);

MS (ESI) m/z 379 (M+H)⁺;

Anal. Cacld for C₁₉H₃₀N₄O₂S: C, 60.29; H, 7.99: N, 14.80. Found: C,59.98; H, 8.34; N 15.11.

Example 621-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

Part A

A solution of mesityl oxide (30.0 mL, 262 mmol) and diethyl oxalate(35.6 mL, 262 mmol) was added dropwise to a stirred solution of sodiumtert-butoxide (54.1 g, 563 mmol) in ethanol (187 mL) at ambienttemperature according to the procedure described in Part B of Example60. The reaction was stirred for 1 hour, then was treated with aceticacid (131 mL), potassium acetate (38.6 g, 393 mmol), and ethylhydrazineoxalate (43.2 g, 288.2 mmol) according to the procedure described inPart B of Example 60. The mixture was stirred overnight at ambienttemperature. The volatiles were removed under reduced pressure and theresidue was diluted with water and chloroform. 2 M aqueous sodiumcarbonate was added until pH 11 was reached. The mixture was extractedwith chloroform. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to yield ablack oil that was used without purification in the next step.

Part B

A mixture of the material from Part A, concencentrated ammoniumhydroxide (500 mL) and methanol (200 mL) were stirred at ambienttemperature for 16 hours. A white solid was isolated from the mixture byfiltration. More solid was isolated from the filtrate to yield a totalfor 13.9 g of 1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide.

Part C

A mixture of 1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide(5.0 g, 25.9 mmol) and phosphorous oxychloride (18.5 mL) was heated at90° C. for 20 minutes. The reaction vessel was cooled in an ice bath andreaction mixture was poured over ice (100 mL). The quenched reactionmixture was made basic with 2 M aqueous sodium carbonate and wasextracted with chloroform. The organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carbonitrile, all of whichwas used in the next step.

Part D

A solution of the material from Part C and mCPBA (11.7 g, 34.0 mmol) indichloromethane (115 mL) was stirred at ambient temperature overnight.The resulting mixture was diluted with water and the pH was made basicwith 2 M aqueous sodium carbonate. The solution was extracted withchloroform. The combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure to yield5-(3,3-dimethyloxiran-2-yl)-1-ethyl-1H-pyrazole-3-carbonitrile, all ofwhich was used in the next step.

Part E

Bromine (1.7 mL, 33.0 mmol) was added to a solution of the material fromPart D in chloroform at 0° C. The red solution was stirred at ambienttemperature for 2 hours, then saturated aqueous sodium bisulfite wasadded and the mixture was concentrated under reduced pressure. Theresidue was diluted with chloroform (100 mL) and the pH was adjustedwith 2 M aqueous sodium carbonate to pH 11. The cloudy mixture wasdiluted with water (50 mL) and was extracted with chloroform (3×75 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated under reduced pressure to yield 4.4 g of a cloudy oilthat was used without purification in the next step.

Part F

To a mixture of the material from Part E in toluene (62 mL) at ambienttemperature was added azobisisobutyronitrile (AIBN, 512 mg, 3.12 mmol)and tributyltin hydride (4.0 mL, 15.0 mmol). Bubbles were observed for ashort period of time. The pale yellow solution was heated at 90° C. for1 hour. The solution was allowed to cool to ambient temperature andsubjected to chromatography on a HORIZON HPFC system (silica gel,gradient elution with 0-50% ethyl acetate in hexanes to afford 1.1 g of4-bromo-1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrileas a colorless oil.

Part G

To a mixture of4-bromo-1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile(1.0 g, 3.7 mmol) and powdered molecular sieves (1 g) in toluene (23 mL)was added 2-aminophenylboronic acid hydrochloride (1.28 g, 7.4 mmol),potassium phosphate (3.92 g, 18.5 mmol),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (96 mg, 0.093mmol) and bis(2-diphenylphosphinophenyl)ether (60 mg, 0.111 mmol).Nitrogen gas was bubbled through the mixture for 5 minutes. The mixturewas heated at 110° C. for 1 day. After cooling to ambient temperature,the mixture was filtered through a plug of silica gel, which was rinsedwith a solution of 3:2 chloroform/methanol. The filtrate wasconcentrated under reduced pressure to yield a residue that was used inthe next step.

Part H

The material from Part G was dissolved in ethanol (20 mL) and a solutionof hydrogen chloride in ethanol (4 M, 2.8 mL, 11 mmol) was added. Thesolution was heated at reflux for 2 hours. Upon cooling to ambienttemperature, the solution was concentrated under reduced pressure. Tothe resulting oil was added 2 M aqueous sodium carbonate until the pHwas basic, then brine was added and the mixture was extracted withchloroform. The organic layers were combined, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 0-30% CMA in chloroform) then was recrystallizedfrom acetonitrile to yield 0.2 g of1-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas light tan crystals, mp 223-225° C.

MS (APCI) m/z 285 (M+H)⁺;

Anal. calcd for C₁₆H₂₀N₄O: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.38;H, 7.39; N, 19.94.

Example 632-Ethyl-1-[4-(4-pyridin-2-ylpiperazin-1-yl)butyl]-2H-pyrazolo[3,4-c]quinolin-4-amine

A mixture of1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinoline-4-amine (preparedas described in Example 19, 1.0 g, 3.3 mmol), 1-(2-pyridyl)piperazine(0.752 mL, 4.95 mmol), potassium carbonate (1.8 g, 13.2 mmol), andsodium iodide (123 mg, 0.825 mmol) in DMF (6 mL) was heated at 60° C.for 1 hour, then at 90° C. for 2 hours. The reaction was allowed to coolto ambient temperature and white solid formed. Water (100 mL) was addedto the mixture. The mixture was stirred for 30 min and the solid wasisolated by filtration and dried to yield 1.4 g of2-ethyl-1-[4-(4-pyridin-2-ylpiperazin-1-yl)butyl]-2H-pyrazolo[3,4-c]quinolin-4-aminemonohydrate as a white solid, mp 183-184° C.

MS (APCI) m/z 430 (M+H)⁺;

Anal. calcd for C₂₅H₃₁N₇H₂O: C, 67.09; H, 7.43; N, 21.91. Found: C,66.86; H, 7.66; N 22.11.

Example 641-(2-Amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A neat mixture of tert-butyl 1,1-dimethyl-3-oxobutylcarbamate (preparedas described in B. Peschke et al., Eur. J. Med. Chem., 1999, 34,363-380, 14.0 g, 65.0 mmol) and diethyl oxalate (9.50 g, 65.0 mmol) wasadded in one portion, followed by an ethanol rinse (20 mL), to a stirredsolution of sodium tert-butoxide (6.25 g, 65.0 mmol) in ethanol (46 mL).A precipitate formed immediately. The mixture was stirred for 2 hours,then acetic acid (66.4 mL) was added. The resulting solution was cooledto 10° C. and propylhydrazine oxalate (10.7 g, 65.0 mmol) was added inone portion. The reaction was stirred for 45 minutes and the internaltemperature reached 19° C. The volatiles were removed under reducedpressure and water was added. The mixture was stirred while 2 M aqueoussodium carbonate was added until carbon dioxide evolution ceased. Themixture was extracted three times with tert-butyl methyl ether. Theorganic layers were combined, dried over magnesium sulfate, filtered,and concentrated to yield 17.9 g of a yellow solid that wasrecrystallized from hexanes (130 mL). The crystals were isolated byfiltration, washed with cold hexanes, and dried to yield 11.68 g ofethyl5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylateas a white solid, mp 109-111° C. MS (APCI) m/z 354 (M+H)⁺; Anal. cacldfor C₁₈H₃₁N₃O₄: C, 61.17; H, 8.84; N, 11.89. Found: C, 61.18; H, 9.17;N, 11.97.

Part B

Methanol (39.9 mL), lithium hydroxide (5.06 g, 121 mmol), and water(13.3 mL) were added to ethyl5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylate(10.65 g, 30.1 mmol) in a 500 mL round bottom flask. The mixture wasstirred vigorously for 5.5 hours. Acetic acid (8.0 mL) and water (200mL) were added. A white solid formed and more acetic acid (61 mL) wasadded. The solid was isolated by filtration, washed with water, anddried. A second crop of solid was isolated from the filtrate. The cropswere combined to yield 8.77 g of5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylicacid as a white solid, mp 151-152° C. MS (APCI) m/z 326 (M+H)⁺; Anal.calcd for C₁₆H₂₇N₃O₄: C, 59.06; H, 8.36; N, 12.91. Found: C, 58.93; H,8.59; N, 12.94.

Part C

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.68 g,29.6 mmol) was added to a solution of 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-propyl-1H-pyrazole-3-carboxylicacid (8.77 g, 27.0 mmol) and 1-hydroxybenzotriazole (4.00 g, 29.6 mmol)in DMF (44 mL) at ambient temperature. The mixture was stirred for 5.5hours until a solution formed, then was cooled in an ice bath.Concentrated ammonium hydroxide (5.5 mL) was added and the cloudysolution was stirred for 10 minutes, then was allowed to warm to ambienttemperature and stir overnight. Water (150 mL) was added and the mixturewas extracted with chloroform (4×75 mL). The organic layers werecombined, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was concentrated twice from xylene underreduced pressure to afford an oil that was purified on chromatography ona HORIZON HPFC system (silica gel, elution with ethyl acetate) to yield8.21 g of tert-butyl2-[3-(aminocarbonyl)-1-propyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamateas a white solid.

Part D

A solution of trifluoroacetic anhydride (3.93 mL, 27.8 mmol) indichloromethane (51 mL) was added slowly to a 0° C. solution oftert-butyl2-[3-(aminocarbonyl)-1-propyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate(8.21 g, 25.3 mmol) and triethylamine (10.6 mL, 75.9 mmol) indichloromethane (51 mL). After the addition was complete, the coolingbath was removed and the solution was stirred for 90 minutes. Thesolution was transferred to a separatory funnel and washed with 2 Maqueous sodium carbonate (200 mL). The aqueous layer was extracted twicewith chloroform. The organic layers were combined, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to yield anoff white solid that was recrystallized from 10% ethyl acetate inhexanes, isolated by filtration, and dried to yield 6.77 g of tert-butyl2-(3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate as awhite crystals, mp 115-116° C. MS (ESI) m/z 307 (M+H)⁺; Anal. Calcd forC₁₆H₂₆N₄O₂: C, 62.72; H, 8.55; N, 18.28. Found: C, 62.61; H, 8.46; N,18.52.

Part E

tert-Butyl2-(3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate (5.15 g,16.8 mmol) was brominated using a modified version of the methoddescribed in Part F of Examples 14. In the reaction, 1.4 equivalents ofbromine were used instead of 1.1 equivalents, chloroform was usedinstead of dichloromethane in the work-up, and no chromatographicpurification was performed. The product, tert-butyl2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate(6.97 g), was isolated as a clear, colorless oil that may have containedsome chloroform.

Part F

The material from Part E (approximately 16.8 mmol) was dissolved in1-propanol and concentrated under reduced pressure twice, then wasdiluted with approximately 29 mL of 1-propanol. To the resultingsolution was added 2 M aqueous sodium carbonate (25.2 mL, 50.4 mmol),then water (5.88 mL), triphenylphosphine (397 mg, 1.51 mmol), palladium(II) acetate (113 mg, 0.504 mmol), and 2-aminophenylboronic acidhydrochloride (4.37 g, 25.2 mmol). The flask was equipped with a refluxcondenser with a nitrogen inlet and was placed under vacuum andback-filled with nitrogen four times. The reaction was heated under anitrogen atmosphere at 100° C. for 8 hours. The reaction was allowed tocool to ambient temperature and tetrakis(triphenylphosphine)palladium(0)(388 mg), 2 M aqueous sodium carbonate (25.2 mL), and2-aminophenylboronic acid hydrochloride (4.37 g) were added. The mixturewas heated at 100° C. for 11 hours. The reaction was allowed to cool toambient temperature, then was extracted with chloroform four times. Theorganic layers were combined, dried over magnesium sulfate, filtered,and concentrated to yield a brown oil. The crude product was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 40-50% ethyl acetate in hexanes followed by 20% CMA in chloroform).The appropriate fractions were combined and concentrated to yield an oilthat was purified again by chromatography on a HORIZON HPFC system(silica gel, gradient elution with 35-40% ethyl acetate in hexanes) toafford 2.65 g of a light brown oil.

Part G

A solution of the material from Part F in 1 M HCl in ethanol (50 mL) washeated at reflux for 3 hours, then was allowed to stand at ambienttemperature overnight before being concentrated under reduced pressureto yield a solid suspended in ethanol (approximately 5 mL). Thesuspension was cooled in an ice bath and diethyl ether (75 mL) wasadded. The solid was collected by filtration, washed with diethyl ether,and dried to yield 2.3 g of a white solid. The solid was dissolved inwater and 2 M aqueous sodium carbonate was added. The mixture wasextracted with chloroform five times. The organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressure toyield a white solid that was purified by chromatography on a HORIZONHPFC system (silica gel, gradient elution with 20-30% CMA inchloroform). The appropriate fractions were combined and concentrated toa volume of a few mL. A solid was precipitated with hexanes and wasisolated by filtration and dried. The white powder was recrystallizedform aceonitrile to yield 1.17 g of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas white granular crystals, mp 193-195° C.

MS (APCI) m/z 298 (M+H)⁺;

Anal. Calcd for C₁₇H₂₃N₅: C, 68.66; H, 7.80; N, 23.55. Found: C, 68.59;H, 7.50; N, 23.30.

Example 65N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide

Acetyl chloride (221 μL, 3.14 mmol) was added to a 0° C. stirredsolution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 840 mg, 2.82 mmol) andtriethylamine (591 μL, 4.24 mmol) in dichloromethane (25.2 mL). Thesolution was stirred for 20.5 h at ambient temperature, then wasconcentrated under reduced pressure to yield a foam that was dissolvedin methanol. To the solution was added concentrated hydrochloric acid (2mL). The solution was stirred at ambient temperature for 90 minutes,then heated at reflux for 40 minutes. After cooling to ambienttemperature, the solution was concentrated under reduced pressure and 2M aqueous sodium carbonate was added until the pH was basic. Thesolution was extracted with chloroform. The organic layers were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was dissolved in dichlormethane (10 mL), then triethylamine(786 mL) and acetyl chloride (300 mL) were added. The reaction wasworked up as before, then methanol (20 mL) and concentrated hydrochloricacid (2 mL) were added. The solution was heated at reflux for 30minutes, left to stand at ambient temperature overnight, then heated atreflux again for 30 minutes. After cooling to ambient temperature, thesolution was concentrated under reduced pressure and 2 M aqueous sodiumcarbonate was added until the pH was adjusted to pH 10-11. The solutionwas extracted with chloroform three times. The organic layers were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified twice by chromatography on a HORIZON HPFCsystem (silica gel, gradient elution with 20-30% CMA in chloroform forthe first column; gradient elution with 4-10% methanol in chloroform forthe second column). The appropriate fractions were combined andconcentrated under reduced pressure to yield a colorless foam that wascrystallized from ethyl acetate/hexanes. A white solid was isolated anddried under vacuum at elevated temperature to yield 698 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]acetamideas a white solid, mp 182-183° C.

MS (APCI) m/z 340 (M+H)⁺;

Anal. Calcd for C₁₉H₂₅N₅O.0.25H₂O: C, 66.35; H, 7.47; N, 20.36. Found:C, 66.29; H, 7.68; N, 20.09.

Example 66N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide

Methanesulfonyl chloride (232 μL, 3.00 mmol) was added to a 0° C.stirred solution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 892 mg, 3.00 mmol) andtriethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3hours at 0° C., the solution was stirred for 2 days at ambienttemperature. To the solution was added 2 M aqueous sodium carbonate. Themixture was extracted with chloroform four times. The organic layerswere combined, dried over sodium sulfate, filtered, and concentratedunder reduced pressure to yield a white solid. The crude product waspurified by IFC (silica gel, elution with 10% CMA in chloroform). Theappropriate fractions were combined and concentrated under reducedpressure to provide a white foam that was crystallized fromacetonitrile, isolated by filtration, and dried to yield 600 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamideas a white solid, mp 130-139° C.

MS (APCI) m/z 376 (M+H)⁺;

Anal. Calcd for C₁₈H₂₅N₅O₂S.0.25H₂O: C, 56.89; H, 6.76; N, 18.43. Found:C, 56.85; H, 7.09; N, 18.40.

Example 67N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide

Cyclohexanecarbonyl chloride (401 μL, 3.00 mmol) was added to a 0° C.stirred solution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 892 mg, 3.00 mmol) andtriethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3hours at 0° C., the solution was stirred for 2 days at ambienttemperature. More triethylamine (697 μL) and cyclohexanecarbonylchloride (602 μL) was added. After 30 minutes, 2 M aqueous sodiumcarbonate was added to the solution. The mixture was extracted withchloroform four times. The organic layers were combined, dried oversodium sulfate, filtered, and concentrated under reduced pressure.Methanol (20 mL) and concentrated hydrochloric acid (2 mL) were added.The solution was heated at reflux for 4 hours, then left to stand atambient temperature overnight, then heated at reflux again for briefperiods of time during the next 2 days. In all, the solution was heatedat reflux for a total of 7 hours. After cooling to ambient temperature,2 M aqueous sodium carbonate was added to adjust the mixture to pH10-11. The mixture was concentrated under reduced pressure to remove themethanol. Water was added and a solid was isolated from the mixture byfiltration. The solid was washed with water. Chloroform was added to thesolid, and the mixture was filtered. The filtrate was concentrated underreduced pressure and purified by IFC. The appropriate fractions werecombined and concentrated to a white solid that was recrystallized from50% ethyl acetate/hexanes. The crystals were isolated by filtration anddried to yield 896 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamideas a white solid, mp 190-191° C.

MS (APCI) m/z 408 (M+H)⁺;

Anal. Calcd for C₂₄H₃₃N₅O: C, 70.73; H, 8.16; N, 17.18. Found: C, 70.58;H, 8.30; N, 16.91.

Example 68N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]nicotinamide

Nicotinoyl chloride hydrochloride (1.62 g, 9.08 mmol) was added to astirred solution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 1.08 g, 3.63 mmol) andtriethylamine (2.8 mL, 20 mmol) in dichloromethane (32.4 mL). After 2 h,the solution was concentrated under reduced pressure. The residue wasdissolved in methanol (20 mL). Concentrated hydrochloric acid (4 mL) wasadded and the solution was heated at reflux for 30 minutes, then wasallowed to cool to ambient temperature. To the solution was added 2 Maqueous sodium carbonate until the pH was basic, then water was added.The mixture was extracted with chloroform four times. The organic layerswere combined, dried over sodium sulfate, filtered, and concentrated toyield a brown oil that was purified by IFC (silica gel, elution with CMAin chloroform). The appropriate fractions were combined and concentratedto produce a yellow foam that was crystallized from ethylacetate/hexanes. The solid was isolated by filtration and dried to yield418 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]nicotinamideas a pale yellow solid, mp 203-205° C.

MS (APCI) m/z 403 (M+H)⁺;

Anal. Calcd for C₂₃H₂₆N₆O.1.5H₂O: C, 64.31; H, 6.80; N, 19.57. Found: C,64.06; H, 6.56; N, 19.64.

Example 69N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-2-methylpropanamide

2-Methylpropanoyl chloride (786 μL, 7.50 mmol) was added to a 0° C.stirred solution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 892 mg, 3.00 mmol) andtriethylamine (1.32 mL, 9.5 mmol) in dichloromethane (26.7 mL). After 10minutes at 0° C., the solution was stirred for 2 hours at ambienttemperature. The solution was concentrated to afford a white solid thatwas dissolved in methanol (20 mL) and concentrated hydrochloric acid (4mL). The solution was heated at reflux for 3.5 hours, then was left tostand at ambient temperature overnight. To the solution was added 2 Maqueous sodium carbonate until the pH was basic. The mixture wasconcentrated under reduced pressure to remove the methanol. The mixturewas extracted with chloroform four times. The organic layers werecombined, dried over sodium sulfate, filtered, and concentrated to yieldan off-white solid that was purified by IFC (silica gel, eluted with CMAin chloroform). The appropriate fractions were combined and concentratedunder reduced pressure to yield a white foam that was crystallized from50% ethyl acetate in hexanes. The solid was isolated by filtration,washed with 50% ethyl acetate in hexanes, and dried to yield 815 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-2-methylpropanamideas a white solid, mp 177-178.5° C.

MS (APCI) m/z 368 (M+H)⁺;

Anal. Calcd for C₂₁H₂₉N₅O: C, 68.64; H, 7.95; N, 19.06. Found: C, 68.49;H, 8.23; N, 18.97.

Example 70N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea

Isopropyl isocyanate (255 mg, 3.00 mmol) was added to a 0° C. stirredsolution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 892 mg, 3.00 mmol) indichloromethane (26.7 mL). After 4 hours at 0° C., the solution wasstirred overnight at ambient temperature. The solution was concentratedto afford a colorless resin that was purified by IFC (silica gel,elution with CMA in chloroform). The appropriate fractions were combinedand concentrated to yield a solid that was recrystallized from ethylacetate in hexanes. The solid was isolated by filtration, washed withethyl acetate/hexanes, and dried to yield 130 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-N,′-isopropylureaas a white solid, mp 190-191° C.

MS (APCI) m/z 383 (M+H)⁺;

Anal. Calcd for C₂₁H₃₀N₆O.0.25H₂O: C, 65.17; H, 7.94; N, 21.72. Found:C, 65.15; H, 8.03; N, 21.76.

Examples 71-85

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared asdescribed in Example 9, 23 mg, 0.10 mmol) and potassium carbonate(approximately 40 mg, 0.29 mmol) in DMF (1 mL). A stirbar was added toeach test tube. The test tubes were capped and stirred overnight atambient temperature. The solvent was removed by vacuum centrifugation.

The compounds were purified by preparative high performance liquidchromatography (prep HPLC) using a Waters FractionLynx automatedpurification system. The prep HPLC fractions were analyzed using aWaters LC/TOF-MS, and the appropriate fractions were centrifugeevaporated to provide the trifluoroacetate salt of the desired compound.Reversed phase preparative liquid chromatography was performed withnon-linear gradient elution from 5-95% B where A is 0.05%trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile. Fractions were collected by mass-selective tiggering.The table below shows the reagent added to each test tube, the structureof the resulting compound, and the observed accurate mass for theisolated trifluoroacetate salt. EXAMPLES 71-85

Ex- Measured am- Mass ple Reagent R (M + H) 71 none —H 241.1455 72Benzyl bromide

331.1935 73 1-Bromopropane

283.1894 74 1-Bromopentane

311.2221 75 5-Bromovaleronitrile

322.2037 76 2-Iodobutane

297.2060 77 4-Methylbenzyl bromide

345.2080 78 4-Cyanobenzyl bromide

356.1867 79 1-Iodo-3-methylbutane

311.2220 80 3-Methoxybenzyl bromide

361.2035 81 beta-Bromophenetole

361.2040 82 4-Chlorobenzyl bromide

365.1545 83 Methyl 4- (bromomethyl)benzoate

389.1986 84 4- (Trifluoromethyl)benzyl bromide

399.1820 85 3,4-Dichlorobenzyl bromide

399.1148

Examples 86-197

A regent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-aminoethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride (prepared as described in Parts A-J of Example 50, 31mg, 0.10 mmol) and N,N-diisopropylethylamine (0.069 mL, 0.40 mmol) inDMF (1 mL). The test tubes were capped, shaken for four hours at ambienttemperature. The solvent was removed by vacuum centrifugation. Thecompounds were purified as described in Examples 71-85. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt. EXAMPLES 86-197

Measured Mass Example Reagent R (M + H) 86 none

242.1400 87 Acetylchloride

284.1511 88 Methyl chloroformate

300.1460 89 Cyclopropanecarbonyl chloride

310.1672 90 Butryl chloride

312.1812 91 Ethyl chloroformate

314.1607 92 Methoxyacetyl chloride

314.1599 93 Cyclobutanecarbonyl chloride

324.1807 94 Pivaloyl chloride

326.1982 95 2-Furoyl chloride

336.1455 96 3-Furoyl chloride

336.1483 97 Benzoyl chionde

346.1654 98 Cyclopentylacetyl chloride

352.2130 99 Cyclohexanecarbonyl chloride

352.2140 100 m-Toluoyl chloride

360.1840 101 p-Toluoyl chloride

360.1839 102 Phenylacetyl chloride

360.1836 103 o-Toluoyl chloride

360.1823 104 4-Cyanobenzoyl chloride

371.1636 105 3-Cyanobenzoyl chloride

371.1608 106 Cinnamoyl chloride

372.1824 107 Hydrocinnamoyl chloride

374.1956 108 3-Methoxybenzoyl chloride

376.1795 109 p-Anisoyl chloride

376.1804 110 2-Chlorobenzoyl chloride

380.1255 111 3-Chlorobenzoyl chloride

380.1294 112 4-Chlorobenzoyl chloride

380.1310 113 Isonicotinoyl chloride hydrochloride

347.1617 114 Nicotinoyl chloride hydrochloride

347.1597 115 Picolinoyl chloride hydrochloride

347.1585 116 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

386.1975 117 4-Dimethylaminobenzoyl chloride

389.2125 118 3-Dimethylaminobenzoyl chloride

389.2104 119 (Phenylthio)acetyl chloride

392.1530 120 2-Naphthoyl chloride

396.1837 121 2,4-Dimethoxybenzoyl chloride

406.1906 122 3-(Trifluoromethyl)benzoyl chloride

414.1536 123 3,4-Dichlorobenzoyl chloride

414.0906 124 2,4-Dichlorobenzoyl chloride

414.0908 125 2,6-Dichlorobenzoyl chloride

414.0900 126 3,5-Dichlorobenzoyl chloride

414.0910 127 4-Biphenylcarbonyl chloride

422.2006 128 Methanesulfonyl chloride

320.1184 129 Ethanesulfonyl chloride

334.1332 130 1-Propanesulfonyl chloride

348.1492 131 Isopropylsulfonyl chloride

348.1521 132 Dimethylsulfamoyl chloride

349.1465 133 1-Butanesulfonyl chloride

362.1653 134 Trifluoromethanesulfonyl chloride

374.0889 135 Benzenesulfonyl chloride

382.1341 136 2,2,2-Trifluoroethanesulfonyl chloride

388.1060 137 2-Thiophenesulfonyl chloride

388.0883 138 3-Methylbenzenesulfonyl chloride

396.1499 139 alpha-Toluenesulfonyl chloride

396.1493 140 o-Toluenesulfonyl chloride

396.1525 141 p-Toluenesulfonyl chloride

396.1475 142 2-Fluorobenzenesulfonyl chloride

400.1256 143 3-Fluorobenzenesulfonyl chloride

400.1277 144 4-Fluorobenzenesulfonyl chloride

400.1235 145 3-Cyanobenzenesulfonyl chloride

407.1299 146 4-Cyanobenzenesulfonyl chloride

407.1327 147 beta-Styrenesulfonyl chloride

408.1498 148 3-Methoxybenzenesulfonyl chloride

412.1471 149 4-Methoxybenzenesulfonyl chloride

412.1478 150 2-Chlorobenzenesulfonyl chloride

416.0967 151 3-Chlorobenzenesulfonyl chloride

416.0960 152 4-Chlorobenzenesulfonyl chloride

416.0978 153 1-Naphthalenesulfonyl chloride

432.1494 154 2-Naphthalenesulfonyl chloride

432.1490 155 2,5-Dimethoxybenzenesulfonyl chloride

442.1533 156 Dimethoxybenzenesulfonyl chloride

442.1549 157 3- (Trifluoromethyl)benzenesulfonyl chloride

450.1183 158 2- (Trifluoromethyl)benzenesulfonyl chloride

450.1194 159 4- (Trifluoromethyl)benzenesulfonyl chloride

450.1187 160 2,3-Dichlorobenzenesulfonyl chloride

450.0583 161 2,4-Dichlorobenzenesulfonyl chloride

450.0587 162 2,5-Dichlorobenzenesulfonyl chloride

450.0571 163 2,6-Dichlorobenzenesulfonyl chloride

450.0598 164 3,4-Dichlorobenzenesulfonyl chloride

450.0583 165 10-Camphorsulfonyl chloride

456.2094 166 4- (Trifluoromethoxy)benzenesulfonyl chloride

466.1161 167 Methyl isocyanate

299.1630 168 Ethyl isocyanate

313.1789 169 Isopropyl isocyanate

327.1940 170 Pentyl isocyanate

355.2246 171 Phenylisocyanate

361.1775 172 Cyclohexyl isocyanate

367.2263 173 Benzylisocyanate

375.1959 174 m-Tolyl isocyanate

375.1939 175 o-Tolyl isocyanate

375.1937 176 p-Tolyl isocyanate

375.1939 177 3-Pyridyl isothiocyanate

378.1530 178 4-Cyanophenylisocyanate

386.1752 179 Benzoyl isocyanate

389.1724 180 (R)-(+)-alpha-Methylbenzyl isocyanate

389.2057 181 2-Phenyl ethylisocyanate

389.2061 182 2-Methoxyphenyl isocyanate

391.1881 183 3-Methoxyphenyl isocyanate

391.1856 184 4-Methoxyphenyl isocyanate

391.1888 185 2-Chlorophenyl isocyanate

395.1394 186 3-Chlorophenyl isocyanate

395.1395 187 4-Chlorophenyl isocyanate

395.1357 188 3,4-Difluorophenyl isocyanate

397.1572 189 trans-2-Phenylcyclopropyl isocyanate

401.2105 190 3-Acetylphenyl isocyanate

403.1882 191 1-Naphthyl isocyanate

411.1963 192 2-Morpholinoethyl isothiocyanate

414.2108 193 3-Carbomethoxyphenyl isocyanate

419.1846 194 4-(Dimethylamino)isothiocyanate

420.1989 195 3,4-Dimethoxyphenyl isocyanate

421.1974 196 3,5-Dimethoxyphenyl isocyanate

421.1998 197 4-Methyl-1-piperazinecarbonyl chloride

368.2194

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 50, 25 mg, 0.10 mmol) andN,N-diisopropylethylamine (0.035 mL, 0.20 mmol) in chloroform (1 mL).The test tubes were capped, shaken for four hours at ambienttemperature, and then were shaken overnight. Two drops of water wereadded to each test tube, and the solvent was removed by vacuumcentrifugation. The compounds were purified as described in Examples71-85. The table below shows the reagent added to each test tube, thestructure of the resulting compound, and the served accurate mass forthe isolated trifluoroacetate salt.

Examples 198-270

EXAMPLES 198-270

Measured Mass Example Reagent R (M + H) 198 none

246.1712 199 Acetyl chloride

288.1845 200 Propionyl chloride

302.1989 201 Cyclopropanecarbonyl chloride

314.1982 202 Butyryl chloride

316.2153 203 Methoxyacetyl chloride

318.1920 204 Methyl chlorothiolformate

320.1528 205 Cyclopentylacetyl chloride

356.2448 206 m-Toluoyl chloride

364.2139 207 p-Toluoyl chloride

364.2139 208 Phenylacetyl chloride

364.2135 209 3-Fluorobenzoyl chloride

368.1854 210 4-Fluorobenzoyl chloride

368.1859 211 3-Cyanobenzoyl chloride

375.1942 212 Hydrocinnamoyl chloride

378.2286 213 2-Methoxybenzoyl chloride

380.2076 214 3-Methoxybenzoyl chloride

380.2078 215 p-Anisoyl chloride

380.2050 216 2-Chlorobenzoyl chloride

384.1574 217 Isonicotinoyl chloride hydrochloride

351.1942 218 Nicotinoyl chloride hydrochloride

351.1934 219 Picolinoyl chloride hydrochloride

351.1912 220 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

390.2289 221 3,4-Dimethoxybenzoyl chloride

410.2179 222 3-(Trifluoromethyl)benzoyl chloride

418.1834 223 2,4-Dichlorobenzoyl chloride

418.1243 224 Methanesulfonyl chloride

324.1476 225 Ethanesulfonyl chloride

338.1645 226 1-Propanesulfonyl chloride

352.1780 227 Dimethylsulfamoyl chloride

353.1751 228 1-Butanesulfonyl chloride

366.1972 229 Trifluoromethanesulfonyl chloride

378.1198 230 1-Methylimidazole-4-sulphonyl chloride

390.1730 231 2,2,2-Trifluoroethanesulfonyl chloride

392.1344 232 3-Methylbenzenesulfonyl chloride

400.1787 233 alpha-Toluenesulfonyl chloride

400.1801 234 2-Fluorobenzenesulfonyl chloride

404.1536 235 3-Fluorobenzenesulfonyl chloride

404.1560 236 4-Fluorobenzenesulfonyl chloride

404.1543 237 3-Cyanobenzenesulfonyl chloride

411.1613 238 4-Cyanobenzenesulfonyl chloride

411.1631 239 beta-Styrenesulfonyl chloride

412.1797 240 3-Methoxybenzenesulfonyl chloride

416.1752 241 4-Methoxybenzenesulfonyl chloride

416.1774 242 2-Chlorobenzenesulfonyl chloride

420.1244 243 3-Chlorobenzenesulfonyl chloride

420.1227 244 2-Naphthalenesulfonyl chloride

436.1782 245 N-Acetylsulfanilyl chloride

443.1829 246 3,4-Dimethoxybenzenesulfonyl chloride

446.1832 247 3- (Trifluoromethyl)benzenesulfonyl chloride

454.1510 248 3,4-Dichlorobenzenesulfonyl chloride

454.0905 249 3,5-Dichlorobenzenesulfonyl chloride

454.0891 250 Methyl isocyanate

303.1942 251 Ethyl isocyanate

317.2078 252 Isopropyl isocyanate

331.2234 253 Cyclopropyl isothiocyanate

345.1847 254 Cyclopropylmethyl isothiocyanate

359.2050 255 Phenyl isocyanate

365.2102 256 Benzylisocyanate

379.2238 257 m-Tolyl isocyanate

379.2245 258 p-Tolyl isocyanate

379.2234 259 Phenyl isothiocyanate

381.1844 260 3-Pyridyl isothiocyanate

382.1807 261 3-Methoxyphenyl isocyanate

395.2202 262 4-Methoxyphenyl isocyanate

395.2234 263 3-Chlorophenyl isocyanate

399.1696 264 1-Naphthyl isocyanate

415.2243 265 2-Morpholinoethyl isothiocyanate

418.2388 266 N,N-Dimethylcarbamoyl chloride

317.2071 267 1-Piperidinecarbonyl chloride

357.2418 268 4-Morpholinylcarbonyl chloride

359.2209 269 4-Methyl-1-piperazinecarbonyl chloride

372.2527 270 N-Methyl-N-phenylcarbamoyl chloride

379.2267

Examples 271-306

A reagent (0.14 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared asdescribed in Example 9, 32 mg, 0.13 mmol) and potassium carbonate(approximately 55 mg, 0.40 mmol) in DMF (1 mL). A stirbar was added toeach test tube. The test tubes were capped and stirred overnight(approximately 18 horus) at ambient temperature. The reaction mixtureswere filtered and the solvent was removed from the filtrates by vacuumcentrifugation. The compounds were purified as described in Examples71-85. The table below shows the reagent added to each test tube, thestructure of the resulting compound, and the observed accurate mass forthe isolated trifluoroacetate salt. EXAMPLES 271-306

Measured Example Reagent R Mass (M + H) 271 2-Bromoethyl methyl ether

299.1857 272 Iodomethane

255.1599 273 Cyclobutylmethyl bromide

309.2067 274 2-Bromopropanamide

312.1841 275 Methyl bromoacetate

313.1661 276 Iodoethane

269.1758 277 2-Iodoethanol

285.1724 278 2-Bromo-4-hydroxvaleric acid gamma-lactone

339.1794 279 1-Iodobutane

297.2073 280 (1-Bromoethyl)benzene

345.2084 281 alpha-Bromo-m-xylene

345.2065 282 alpha-Bromo-o-xylene

345.2049 283 Iodoacetic acid

299.1503 284 2-Cyclohexylethyl bromide

351.2532 285 alpha-Bromo-m-tolunitrile

356.1871 286 2-Chlorobenzyl bromide

365.1530 287 3-Chlorobenzyl bromide

365.1534 288 2,3-Difluorobenzyl bromide

367.1741 289 2,4-Difluorobenzyl bromide

367.1734 290 2,6-Difluorobenzyl bromide

367.1718 291 3,4-Difluorobenzyl bromide

367.1704 292 4-Nitrobenzyl bromide

376.1784 293 2-(Bromomethyl)naphthalene

381.2071 294 1-Iodo-3,3,3-trifluoropropane

337.1628 295 4-(tert-Butyl)benzyl bromide

387.2564 296 Methyl (bromomethyl)benzoate

389.1986 297 2-(Trifluoromethyl)benzyl bromide

399.1796 298 3-(Trifluoromethyl)benzyl bromide

399.1790 299 2,6-Dichlorobenzyl bromide

399.1157 300 4-Bromomethylbiphenyl

407.2252 301 Bromodiphenylmethane

407.2248 302 3-(Trifluoromethoxy)benzyl bromide

415.1747 303 4-(Trifluoromethoxy)benzyl bromide

415.1759 304 1-Adamantyl bromomethyl ketone

417.2643 305 4-(Bromomethyl)benzophenone

435.2195 306 2-(Bromoacetyl)pyridine hydrobromide

332.1870

A solution of1-(2-aminoethyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride (prepared as described in Example 23, 33 mg, 0.10 mmol)and N,N-diisopropylethylamine (0.070 mL, 0.40 mmol) in chloroform (1 mL)was treated with a reagent (0.11 mmol, 1.1 equivalents) from the tablebelow using the procedure described in Examples 23-33. The test tubeswere capped and shaken overnight at ambient temperature, then wereworked up and purified as described in Examples 23-33. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 307-348

EXAMPLES 307-348

Measured Mass Example Reagent R (M + H) 307 Acetyl chloride

298.1668 308 Propionyl chloride

312.1841 309 Methyl chloroformate

314.1601 310 Butryl chloride

326.1995 311 Cyclobutanecarbonyl chloride

338.1966 312 Cyclopentylacetyl chloride

366.2291 313 m-Toluoyl chloride

374.2002 314 3-Cyanobenzoyl chloride

385.1764 315 Hydrocinnamoyl chloride

388.2147 316 3-Methoxybenzoyl chloride

390.1935 317 3-Chlorobenzoyl chloride

394.1436 318 4-Chlorobenzoyl chloride

394.1441 319 Isonicotinoyl chloride hydrochloride

361.1778 320 Picolinoyl chloride hydrochloride

361.1762 321 3-Dimethylaminobenzoyl chloride

403.2254 322 Methanesulfonyl chloride

334.1329 323 Ethanesulfonyl chloride

348.1497 324 1-Propanesulfonyl chloride

362.1642 325 1-Butanesulfonyl chloride

376.1806 326 Trifluoromethanesulfonyl chloride

388.1048 327 1-Methylimidazole-4- sulfonyl chloride

400.1549 328 3-Methylbenzenesulfonyl chloride

410.1651 329 alpha-Toluenesulfonyl chloride

410.1644 330 3-Cyanobenzenesulfonyl chloride

421.1447 331 3-Methoxylbenzenesulfonyl chloride

426.1591 332 3-Chlorobenzenesulfonyl chloride

430.1097 333 Methyl isocyanate

313.1771 334 Ethyl isocyanate

327.1921 335 Methyl isothiocyanate

329.1542 336 Cyclopropyl isothiocyanate

355.1706 337 Pentyl isocyanate

369.2397 338 Cyclopropylmethyl isothiocyanate

369.1848 339 Cyclohexyl isocyanate

381.2404 340 Benzyl isocyanate

389.2104 341 m-Tolyl isocyanate

389.2086 342 Phenyl isothiocyanate

391.1704 343 Cyclohexyl isothiocyanate

397.2166 345 3-Methoxyphenyl isocyanate

405.2052 346 trans-2-Phenylcyclopropyl isocyanate

415.2250 347 4-Morpholinylcarbonyl chloride

369.2028 348 N-Methyl-N- phenylcarbamoyl chloride

389.2051

Examples 349-453

Part A

2-[4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]isoindole-1,3-dione(prepared as described in Example 22, 7.10 g, 17.2 mmol), hydrazinehydrate (4.20 mL, 85.9 mmol), and ethanol (213 mL) were combined andheated at reflux for 30 minutes. The solution was allowed to cool toambient temperature, then was cooled to 0° C. A white solid precipitatedfrom the solution and was isolated by filtration and washed withethanol. The crude product was purified by chromatography on a HORIZONHPFC system (silica, gradient elution with 10%-75% CMA in chloroform).The appropriate fractions were combined and concentrated under reducedpressure to afford 4.25 g of1-(4-aminobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part B

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(4-aminobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (28 mg, 0.10mmol) and N,N-diisopropylethylamine (0.026 mL, 0.15 mmol) in chloroform(1 mL). The test tubes were capped and the test tubes were shakenovernight at room temperature and then two drops of water were added toeach test tube. The solvent was removed by vacuum centrifugation. Thecompounds were purified as described in Examples 71-85. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt. EXAMPLES 349-453

Measured Example Reagent R Mass (M + H) 349 none

284.1877 350 Acetyl chloride

326.1978 351 Propionyl chloride

340.2140 352 Methyl chioroformate

342.1937 353 Cyclopropanecarbonyl chloride

352.2149 354 Butyryl chloride

354.2276 355 Methoxyacetyl chloride

356.2112 356 Cyclobutanecarbonyl chloride

366.2305 357 Pivaloyl chloride

368.2444 358 3-Furoyl chloride

378.1927 359 Hexanoyl chloride

382.2627 360 Benzoyl chloride

388.2150 361 Cyclohexanecarbonyl chloride

394.2607 362 m-Toluoyl chloride

402.2298 363 p-Toluoyl chloride

402.2291 364 Phenylacetyl chloride

402.2286 365 4-Cyanobenzoyl chloride

413.2110 366 3-Cyanobenzoyl chloride

413.2065 367 Cinnamoyl chloride

414.2303 368 Hydrocinnamoyl chloride

416.2462 369 2-Methoxybenzoyl chloride

418.2260 370 3-Methoxybenzoyl chloride

418.2227 371 Benzyl chloroformate

418.2251 372 p-Anisoyl chloride

418.2253 373 2-Chlorobenzoyl chloride

422.1730 374 3-Chlorobenzoyl chloride

422.1746 375 4-Chlorobenzoyl chloride

422.1752 376 Isonicotinoyl chloride hydrochloride

389.2069 377 Nicotinoyl chloride hydrochloride

389.2081 378 Picolinoyl chloride hydrochloride

389.2097 379 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

428.2440 380 3-Dimethylaminobenzoyl chloride

431.2560 381 2-Naphthoyl chloride

438.2295 382 3,4-Dimethoxybenzoyl chloride

448.2343 383 3-(Trifluoromethyl)benzoyl chloride

456.2019 384 4-Biphenylcarbonyl chloride

464.2492 385 3-(Trifluoromethoxy)benzoyl chloride

472.1953 386 Methanesulfonyl chloride

362.1651 387 Ethanesulfonyl chloride

376.1832 388 1-Propanesulfonyl chloride

390.1955 389 Isopropanesulfonyl chloride

390.1954 390 Dimethylsulfamoyl chloride

391.1898 391 1-Butanesulfonyl chloride

404.2154 392 Trifluoromethanesulfonyl chloride

416.1362 393 Benzenesulfonyl chloride

424.1826 394 1-Methylimidazole-4-sulfonyl chloride

428.1883 395 2,2,2-Trifluoroethanesulfonyl chloride

430.1515 396 3-Methylbenzenesulfonyl chloride

438.1981 397 alpha-Toluenesulfonyl chloride

438.1944 398 p-Toluenesulfonyl chloride

438.2003 399 3-Fluorobenzenesulfonyl chloride

442.1712 400 4-Fluorobenzenesulfonyl chloride

442.1740 401 3-Cyanobenzenesulfonyl chloride

449.1736 402 4-Cyanobenzenesulfonyl chloride

449.1800 403 beta-Styrenesulfonyl chloride

450.1969 404 3-Methoxybenzenesulfonyl chloride

454.1942 405 4-Methoxybenzenensulfonyl chloride

454.1910 406 2-Chlorobenzenesulfonyl chloride

458.1417 407 3-Chlorobenzenesulfonyl chloride

458.1423 408 4-Chlorobenzenesulfonyl chloride

458.1418 409 2-Naphthalenesulfonyl chloride

474.1969 410 3,4-Dichlorobenzenesulfonyl chloride

492.1036 411 10-Camphorsulfonyl chloride

498.2510 412 3-(Trifluoromethoxy)benzenesulphonyl

508.1635 413 Methyl isocyanate

341.2076 414 Ethyl isocyanate

355.2278 415 Methyl isothiocyanate

357.1883 416 Isopropyl isocyanate

369.2388 417 Ethyl isothiocyanate

371.2035 418 Cyclopropyl isothiocyanate

383.2018 419 Isopropyl isothiocyanate

385.2171 420 Pentyl isocyanate

397.2738 421 Cyclopropyl isothiocyanate

397.2174 422 Isobutyl isothiocyanate

399.2336 423 Phenyl isocyanate

403.2256 424 Cyclohexyl isocyanate

409.2725 425 Benzyl isocyanate

417.2388 426 m-Tolyl isocyanate

417.2409 427 o-Tolyl isocyanate

417.2403 428 p-Tolyl isocyanate

417.2428 429 Phenyl isothiocyanate

419.2035 430 3-Pyridyl isothiocyanate

420.1951 431 Benzoyl isocyanate

431.2180 432 2-Phenylethyl isocyanate

431.2529 433 2-Methoxyphenyl isocyanate

433.2350 434 3-Methoxyphenyl isocyanate

433.2338 435 4-Methoxyphenyl isocyanate

433.2359 436 2-(Thien-2-yl)ethyl isocyanate

437.2132 437 2-Chlorophenyl isocyanate

437.1870 438 3-Chlorophenyl isocyanate

437.1870 439 4-Chlorophenyl isocyanate

437.1896 440 3,4-Difluorophenyl isocyanate

439.2064 441 trans-2-Phenylcyclopropyl isocyanate

443.2563 442 3-Cyanophenyl isothiocyanate

444.1997 443 3-Acetyiphenyl isocyanate

445.2336 444 2-Morpholinoethyl isothiocyanate

456.2535 445 3-Carbomethoxyphenyl isocyanate

461.2263 446 4-(Dimethylamino)phenyl isocyanate

462.2433 447 N,N-Dimethylcarbamoyl chloride

355.2226 448 Dimethylthiocarbamoyl chloride

371.2020 449 1-Piperidinecarbonyl chloride

395.2556 450 2-Oxo-1-imidazolidinecarbonyl chloride

396.2154 451 4-Methyl-1-piperazinecarbonyl chloride

410.2647 452 N-Methyl-N-phenylcarbamoyl chloride

417.2386 453 N-Methyl-N-phenylthiocarbamoyl chloride

433.2192

Example 454-488

Part A

Ethyl 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxylate was preparedfrom 6-chloro-2-hexanone (50.0 g, 357 mmol) and diethyl oxalate (48.4mL, 357 mmol) according to the procedure described in Part A of Example19 using methyl hydrazine (19.0 mL, 357 mmol) in place of ethylhydrazineoxalate. Ethyl 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxylate wasisolated as a dark oil that was used without purification in the nextstep.

Part B

The material from Part A was converted into ethyl5-[4-(acetyloxy)butyl]-1-methyl-1H-pyrazole-3-carboxylate according tothe procedure used in Part B of Example 19. The crude product was usedwithout purification in the next step.

Part C

A solution of the material from Part B in methanol (175 mL) was treatedwith ammonium hydroxide (250 mL) according to a modification of themethod described in Part D of Examples 1-4. The reaction was heatedovernight at 125° C. and allowed to cool to ambient temperature. Themethanol and water were removed under reduced pressure. Acetonitrile wasadded and the mixture was filtered through a plug of silica gel (elutedwith 20% methanol in chloroform). The filtrate was concentrated to yield5-(4-hydroxybutyl)-1-methyl-1H-pyrazole-3-carboxamide that was used inthe next step without further purification.

Part D

A modification of the method described in Part E of Examples 1-4 wasused to treat 5-(4-hydroxybutyl)-1-methyl-1H-pyrazole-3-carboxamide(42.9 g, 218 mmol) with phosphorous oxychloride (130 mL). The reactionwas heated for two hours at 90° C. before cooling to 0° C. and pouringinto ice water. The mixture was adjusted to pH 12 with the addition of 2N aqueous sodium carbonate and 50% aqueous sodium hydroxide. The mixturewas extracted with chloroform. The combined extracts were passed througha layer of silica gel (eluting first with chloroform and then with ethylacetate to provide 23.0 g of5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile as a dark oil thatwas used in the next step without further purification.

Part E

A modification of the method described in Part E of Example 19 was usedto convert the material from Part D (23.0 g) into4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile. Thereaction was allowed to stir for one day before an aqueous solution ofsodium bisulfite was added to quench the excess bromine. The reactionwas worked up as described for Part E of Example 19, except that afterthe combined organic layers were dried over sodium sulfate, they werepassed through a plug of silica gel (eluted with 1:1 ethylacetate/hexanes). The filtrate was concentrated and the crude productwas purified by chromatography on a HORIZON HPFC system (silica gel,gradient elution with 10-50% ethyl acetate/hexanes. The appropriatefractions were combined and concentrated to yield 7.3 g of4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile as a clearoil.

Part F

2-Aminophenylboronic acid hydrochloride (9.20 g, 53.0 mmol), potassiumphosphate (28.0 g, 133 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (685 mg, 0.662 mmol), andbis[(2-diphenylphosphino)phenyl]ether (428 mg, 0.795 mmol) were added toa mixture of4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile (7.30 g,26.5 mmol) and powdered molecular sieves (1 g) in toluene (165 mL).Nitrogen was bubbled through the reaction mixture, and then the reactionwas heated at 110° C. for 24 hours. The mixture was filtered through alayer of silica gel (eluting with 3:2 chloroform/methanol). The filtratewas concentrated under reduced pressure and dissolved in ethanol (130mL). Hydrogen chloride (20 mL of a 4 M solution in ethanol) was added tothe solution and the reaction was heated at reflux for two hours andallowed to cool to ambient temperature. The reaction was worked up asdescribed in Part F of Example 19. After purification by chromatographyon a HORIZON HPFC system, the solid was stirred in acetonitrile andfiltered to provide 1.0 g of1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine that wasused in the next step. The filtrate was concentrated to provide anadditional 4.0 g of product.

Part G

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (29 mg,0.10 mmol) and potassium carbonate (approximately 55 mg, 0.40 mmol) inDMF (1 mL). The test tubes were capped and heated at 100° C. forapproximately 22 hours. The reaction mixtures were filtered and thesolvent was removed from the filtrates by vacuum centrifugation. Thecompounds were purified as described in Examples 71-85. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt. EXAMPLES 454-488

Measured Example Reagent R Mass (M + H) 454 none

289.1205 455 Piperidine

338.2332 456 (R)-3-Hydroxypyrrolidine

340.2130 457 Morpholine

340.2120 458 Thiazolidine

342.1721 459 1-Methylpiperazine

353.2425 460 4-Hydroxypiperidine

354.2310 461 3-Hydroxypiperidine

354.2268 462 Thiomorpholine

356.1884 463 N-Methylfurfurylamine

364.2134 464 N,N′-Dimethyl-3- aminopyrrolidine

367.2619 465 2,6-Dimethylmorpholine

368.2448 466 2-Piperidinemethanol

368.2426 467 3-(Hydroxymethyl)piperidine

368.2443 468 4-(Hydroxymethyl)piperidine

368.2437 469 3-Azabicyclo[3.2.2]nonane

378.2622 470 1-Acetylpiperazine

381.2406 471 Isonipecotamide

381.2375 472 Nipecotamide

381.2426 473 1-Methyl-4- (methylamino)piperidine

381.2733 474 Nipecotic acid

382.2213 475 N-(2-Hydroxyethyl)piperazine

383.2571 476 1,2,3,4-Tetrahydroisoquinoline

386.2333 477 2-(2- Methylaminoethyl)pyridine

389.2438 478 N-(2- Piperidylmethyl)dimethylamine

395.2915 479 4-(1-Pyrrolidinyl)-piperidine

407.2894 480 1-(2-Ethoxyethyl)piperazine

411.2862 481 1-Phenylpiperazine

415.2572 482 1-(2-Pyrdiyl)piperazine

416.2568 483 4-Benzylpiperidine

428.2816 484 1-(2-Furoyl)piperazine

433.2371 485 2-Piperidin-1-ylmethyl- piperidine

435.3229 486 N,N-Diethylnipecotamide

437.3021 487 N-Isopropyl-1- piperazineacetamide

438.3000 488 1-Cinnamylpiperazine

455.2915

Example 489-518

Part A

Potassium phthalimide (4.90 mg, 26.4 mmol), sodium iodide (495 mg, 3.30mmol), and DMF (22 mL) were added to1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (4.00 g,13.2 mmol, prepared as described in Parts A-F of Examples 454-489), andthe reaction was heated at 90° C. for two hours under a nitrogenatmosphere and allowed to cool to ambient temperature. Water (100 mL)was added and a precipitate formed and was isolated by filtration toyield 3.7 g of2-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dionethat was used in the next step.

Part B

A solution of the material from Part A (3.7 g, 8.9 mmol) and hydrazinehydrate (2.15 mL, 44.5 mmol) in ethanol (111 mL) was heated at refluxfor 30 minutes, then was cooled to 0° C. and a white solid formed. Thesolid was isolated and washed with ethanol. The solid was combined withsome material from another experiment and was purified by chromatographyon a HORIZON HPFC system (silica gel, gradient elution with 5-50% CMA inchloroform). The appropriate fractions were combined, concentrated, andtriturated with acetonitrile to afford a solid that was isolated byfiltration to yield 880 mg of1-(4-aminobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a tanpowder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (dd, J=7.6,1.2 Hz, 1H), 7.48 (dd,J=7.6, 1.2 Hz, 1H), 7.31 (td, J=7.2, 1.5 Hz, 1H), 7.19 (td, J=8.1, 1.4Hz, 1H), 6.62 (br s, 2H), 4.10 (s, 3H), 3.31 (s, 2H), 3.23 (t, J=7.6 Hz,2H), 2.57 (t, J=6.9 Hz, 2H), 1.71 (m, 2H), 1.40 (m, 2H);

MS (APCI) m/z 270 (M+H)⁺.

Part C

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(4-aminobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (27 mg,0.01 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.20 mmol) inchloroform (1 mL). The test tubes were capped and shaken overnight atroom temperature and then two drops of water were added to each testtube. The solvent was removed by vacuum centrifugation. The compoundswere purified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Examples 489-518

Measured Mass Example Reagent R (M + H) 489 none H 270.1720 490 Acetylchloride

312.1822 491 Propionyl chloride

326.1971 492 Cyclopropanecarbonyl chloride

338.1985 493 Butyryl chloride

340.2134 494 Cyclobutanecarbonyl chloride

352.2128 495 3-Chlorobenzoyl chloride

408.1593 496 4-Chlorobenzoyl chloride

408.1610 497 Isonicotinoyl chloride hydrochloride

375.1924 498 Nicotinoyl chloride hydrochloride

375.1945 499 Methanesulfonyl chloride

348.1503 500 Ethanesulfonyl chloride

362.1656 501 1-Propanesulfonyl chloride

376.1838 502 1-Butanesulfonyl chloride

390.1973 503 Trifluoromethanesulfonyl

402.1238 504 Benzenesulfonyl chloride

410.1693 505 3-Fluorobenzenesulfonyl chloride

428.1566 506 3-Cyanobenzenesulfonyl chloride

435.1588 507 3-Chlorobenzenesulfonyl chloride

444.1227 508 Methyl isocyanate

327.1951 509 Ethyl isocyanate

341.2088 510 Isopropyl isocyanate

355.2279 511 Pentyl isocyanate

383.2570 512 Phenyl isocyanate

389.2083 513 Cyclohexyl isocyanate

395.2576 514 Benzyl isocyanate

403.2261 515 2-Phenylethyl isocyanate

417.2420 516 N,N-Dimethylcarbamoyl chloride

341.2114 517 4-Morpholinylcarbonyl chloride

383.2235 518 4-Methyl-1- piperazinecarbonyl chloride

396.2516

Examples 519-572

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing the bis-trifluoroacetic acid salt of1-(2-aminoethyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(50 mg, 0.10 mmol, prepared as described in Example 51) andN,N-diisopropylethylamine (0.070 mL, 0.40 mmol) in chloroform (1 mL).The test tubes were capped and shaken overnight at room temperature andthen two drops of water were added to each test tube. The solvent wasremoved by vacuum centrifugation. The compounds were purified asdescribed in Examples 71-85. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Examples 519-572

Measured Mass Example Reagent R (M + H) 519 none H 274.2038 520 Acetylchloride

316.2154 521 Propionyl chloride

330.2310 522 Cyclopropanecarbonyl chloride

342.2291 523 Butyryl chloride

344.2472 524 Benzoyl chloride

378.2303 525 Cyclopentylacetyl chloride

384.2774 526 Cyclohexanecarbonyl chloride

384.2748 527 Phenylacetyl chloride

392.2445 528 3-Fluorobenzoyl chloride

396.2219 529 4-Fluorobenzoyl chloride

396.2224 530 4-Cyanobenzoyl chloride

403.2255 531 3-Cyanobenzoyl chloride

403.2243 532 3-Methoxybenzoyl chloride

408.2416 533 3-Chlorobenzoyl chloride

412.1931 534 4-Chlorobenzoyl chloride

412.1929 535 Isonicotinoyl chloride hydrochloride

379.2278 536 Nicotinoyl chloride hydrochloride

379.2258 537 Picolinoyl chloride hydrocloride

379.2265 538 Methanesulfonyl chloride

352.1819 539 Ethanesulfonyl chloride

366.1990 540 1-Propanesulfonyl chloride

380.2133 541 Isopropylsulfonyl chloride

380.2134 542 Dimethylsulfamoyl chloride

381.2080 543 1 -Butanesulfonyl chloride

394.2316 544 Trifluoromethanesulfonyl chloride

406.1540 545 Benzenesulfonyl chloride

414.1985 546 1-Methylimidazole-4- sulfonyl chloride

418.2029 547 3-Methylbenzenesulfonyl chloride

428.2123 548 3-Fluorobenzenesulfonyl chloride

432.1890 549 4-Cyanobenzenesulfonyl chloride

439.1953 550 3-Methoxybenzenesulfonyl chloride

444.2095 551 3-Chlorobenzenesulfonyl chloride

448.1604 552 4-Chlorobenzenesulfonyl chloride

448.1575 553 Methyl isocyanate

331.2267 554 Ethyl isocyanate

345.2419 555 Isopropyl isocyanate

359.2592 556 Pentyl isocyanate

387.2903 557 Phenyl isocyanate

393.2431 558 Cyclohexyl isocyanate

399.2892 559 Benzyl isocyanate

407.2554 560 m-Tolyl isocyanate

407.2596 561 3-Pyridyl isothiocycante

410.2142 562 2-Phenylethyl isocyanate

421.2730 563 2-Methoxylphenyl isocyanate

423.2517 564 3-Methoxyphenyl isocyanate

423.2527 565 4-Methoxyphenyl isocyanate

423.2525 566 2-Chlorophenyl isocyanate

427.2018 567 3-Chlorophenyl isocyanate

427.2028 568 3,4-Difluorophenyl isocyanate

429.2248 569 N,N-Dimethylcarbamoyl chloride

345.2408 570 4-Morpholinylcarbonyl chloride

387.2500 571 4-Methyl-1- piperazinecarbonyl chloride

400.2845 572 N-Methyl-N- phenylcarbamoyl chloride

407.2571

Example 573 1,2-Diethyl-7-methoxy-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

To a stirred solution ofN-(2-bromo-5-methoxyphenyl)-2,2-dimethylpropanamide (2.82 g, 9.85 mmol)in tetrahydrofuran (20 mL) at −78° C. was added slowly a solution ofn-butyllithium in hexanes (2.5 M, 8.30 mL, 20.7 mmol). The solution wasstirred for 30 minutes in a ″40° C. bath, then was cooled back to −78°C. Triisopropyl borate (6.82 mL, 29.6 mmol) was added slowly. Thesolution was stirred for 1 hour at −40° C., then was stirred at 0° C.for 30 minutes. Saturated aqueous ammonium chloride was added. Themixture was extracted with diethyl ether. The organic layers werecombined, dried over sodium sulfate, filtered, and concentrated toafford a residue that was triturated with hexanes. The hexanes weredecanted and the residue was stirred in methanol/water to precipitate awhite solid that was isolated by filtration, washed with water, anddried to yield 1.36 g of2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid, m.p.256-257° C. The material was used in the next step without furtherpurification.

Part B

A 50 mL round bottom flask containing a mixture of4-bromo-1,5-diethyl-1H-pyrazole-3-carbonitrile (prepared as described inPart E of Example 11, 1.12 g, 4.91 mmol) and2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid (1.36 g,5.40 mmol) in 1-propanol (25 mL) was evacuated and backfilled withnitrogen. To the flask was added triphenylphosphine (38.6 mg, 0.147mmol), 2 M aqueous sodium carbonate (7.4 mL), water (5 mL), andpalladium (II) acetate (11 mg, 0.048 mmol). The yellow suspension washeated at 100° C. After 3 hours, the reaction mixture was allowed tocool to room temperature, water (10 mL) was added, and the 1-propanolwas removed under reduced pressure. The water layer was extracted withethyl acetate (2×30 mL). The organic layers were combined, washed with 2M aqueous sodium carbonate (50 mL), water (50 mL), and brine (50 mL),then dried over sodium sulfate. The organic layer was concentrated underreduced pressure. The crude product was purified by chromatography on aHORIZON HPFC system (silica gel, gradient elution with 0-40% ethylacetate in hexanes) to provide 0.54 g ofN-[2-(3-cyano-1,5-diethyl-1H-pyrazol-4-yl)-5-methoxyphenyl]-2,2-dimethylpropanamideas a colorless liquid.

MS (ESI) m/z 355.28 (M+H)⁺

Part C

A solution of sodium ethoxide in ethanol (21% by weight, 2.29 mL, 13.9mmol) was added to a solution ofN-[2-(3-cyano-1,5-diethyl-1H-pyrazol-4-yl)-5-methoxyphenyl]-2,2-dimethylpropanamide(0.5 g, 1.41 mmol) in ethanol (10 mL). The reaction mixture was stirredat room temperature for 20 minutes and then heated at reflux overnight.The reaction mixture was allowed to cool to room temperature and wasconcentrated under reduced pressure. The resulting residue wastriturated with water to provide a solid that was isolated byfiltration, washed with water, and dried. The material was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionwith 0-20% CMA in chloroform) followed by crystallization fromacetonitrile to yield 0.23 g of1,2-diethyl-7-methoxy-2H-pyrazolo[3,4-c]quinolin-4-amine as beigeneedles, mp 210-211° C.

¹H NMR (500 MHz, DMSO-d₆) δ 7.8 (d, J=8.7 Hz, 1H), 7.0 (d, J=2.7 Hz,1H), 6.80 (dd, J=8.6, 2.7 Hz, 1H), 7.00 (s, 2H), 4.40 (q, J=7.2 Hz, 2H),3.80 (s, 1H), 3.21 (q, J=7.5 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H), 1.28 (t,J=7.5 Hz, 3H);

13C-NMR (75 MHz, CDCl₃) δ158.0, 151.4, 145.6, 137.9, 135.3, 122.8,116.8, 113.6, 110.6, 108.7, 55.3, 44.7, 18.6, 16.4, 13.6;

MS (ESI) m/z 271.2 (M+H)⁺;

Anal. calcd for C₁₅H₁₈N₄O: C, 66.65; H, 6.71; N, 20.73. Found: C, 66.27;H, 6.59; N, 20.72.

Example 5742-Ethyl-7-methoxy-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Using a modification on the method described in Part B of Example 573,4-bromo-1-ethyl-5-(2-phenylethyl)-1H-pyrazole-3-carbonitrile (preparedas described in Part E of Example 41, 10.3 g, 33.9 mmol) was coupledwith 2-[(2,2-dimethylpropanoyl)amino]-4-methoxyphenylboronic acid(prepared as described in Part A of Example 573, 15.3 g, 60.9 mmol). Thereaction was worked up and purified as described in Part B of Example573 to yield 1.7 g ofN-{2-[3-cyano-1-ethyl-5-(2-phenylethyl)-1H-pyrazol4-yl]-5-methoxyphenyl}-2,2-dimethylpropanamideas a colorless liquid, MS (ESI) m/z 431.17 (M+H)⁺.

Part B

A modification of the method described in Part C of Example 573 was usedto convert the material from Part A into2-ethyl-7-methoxy-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.The crude product was purified by chromatography on a HORIZON HPFCsystem (silica gel, gradient elution with 0-30% CMA in chloroform)followed by crystallization from acetonitrile to yield 0.57 g of2-ethyl-7-methoxy-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amineas an off-white solid, mp 162-163° C. MS (ESI) m/z 347.32 (M+H)⁺; Anal.calcd for C₂₁H₂₂N₄O: C, 72.81; H, 6.40; N, 16.17. Found: C, 72.60; H,6.53; N, 16.32.

Example 5754-Amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-olhydrochloride

2-Ethyl-7-methoxy-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(0.37 g, 1.07 mmol) was added in one portion to boiling pyridiniumchloride (3.70 g, 32.0 mmol). The mixture was heated at reflux for 4hours, and then was allowed to cool to room temperature. The mixture wastriturated with ice water and the precipitate was isolated byfiltration, washed with water, and dried to yield 0.38 g of4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-olhydrochloride as a light grey solid, mp>300° C.

MS (ESI) m/z 333.31 (M+H)⁺;

Anal. calcd for C₂₀H₂₀N₄O.1.1HCl.0.25H₂O: C, 63.72; H, 5.78; N, 14.86;Cl, 10.34. Found: C, 63.75; H, 5.96; N, 15.10; Cl, 10.61.

Example 5764-Amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-yltrifluoromethanesulfonate

N-Phenyl-bis(trifluoromethanesulfonamide (0.187 g, 0.447 mmol) was addedto a stirred solution of4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-olhydrochloride (0.15 g, 0.41 mmol) and triethylamine (0.280 mL, 2.03mmol) in DMF (5 mL). After 6 hours, water (25 mL) was added and aprecipitate formed that was isolated by filtration, washed with water,and dried to yield 0.175 g of4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-yltrifluoromethanesulfonate as a white powder, mp 178-179° C.

¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=8.8 Hz, 1H), 7.43 (d, J=2.7 Hz,1H), 7.25 (m, 6H), 7.09 (s, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.54 (t, J=7.3Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 1.32(t, J=7.2 Hz, 3H).

MS (APCI) m/z 465.13 (M+H)⁺.

Example 577 1-(4-Aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A mixture of potassium phthalimide (6.61 g, 35.7 mmol), sodium iodide(0.669 g, 4.46 mmol) and1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 46, 5.65 g, 17.8 mmol) in DMF (30 mL) was heatedat 90° C. for 3 hours. The reaction mixture was allowed to cool to roomtemperature overnight, then was diluted with ice water (300 mL) andstirred for 10 minutes. A solid formed that was collected by filtrationand dried to yield 7.14 g of2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dioneas a tan solid, mp 204-206° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.86-7.70 (m,5H), 7.69-7.64 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.22 (m, 1H), 5.37 (brs, 2H), 4.30 (t, J=7.3 Hz, 2H), 3.77 (t, J=6.8 Hz, 2H), 3.31-3.21 (m,2H), 2.05-1.75 (m, 6H), 0.98 (t, J=7.4 Hz, 3H).

Part B

A mixture of2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione(7.21 g, 16.9 mmol) and hydrazine hydrate (4.22 g, 84.3 mmol) in ethanol(400 mL) was heated at reflux for 2 hours. The resulting solution wasallowed to cool to room temperature, filtered, and concentrated underreduced pressure to yield 3.52 g of1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a yellowsolid, mp 137-139° C.

MS (APCI) m/z 298.2 (M+H)⁺.

Example 5781-(4-Aminobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A solution of1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (2.40 g,8.06 mmol) in trifluoroacetic acid (20 mL) was treated with platinum(IV) oxide. The mixture was hydrogenated on a Parr apparatus at 50 psi(3.5×10⁵ Pa) for 1 day, and then was diluted with chloroform (50 mL) andmethanol (25 mL). The mixture was filtered through CELITE filter agent.The filtrate was concentrated under reduced pressure to yield 6.0 g thebis-trifluoroacetic acid salt of1-(4-aminobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-aminein residual trifluoroacetic acid as a yellow liquid.

MS (APCI) m/z 302.3 (M+H)⁺.

Examples 579-581

Part A

A solution of 1-butyl-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 43, 1.43 g, 4.60 mmol) in 6 M HCl inwater (40 mL) was heated at 100° C. overnight. The reaction mixture wasallowed too cool to room temperature and a white solid was isolated byfiltration, washed with water to provide1-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride that was usedin the next step without extensive drying. Alternatively, the productcan be dried in a vacuum oven at 95° C.

Anal. calcd for C₁₄H₁₆N₄.0.8 HCl: C, 56.31; H. 5.67; N, 18.76. Found: C,56.64; H, 5.10; N, 18.68.

Part B

A solution of 1-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride(1 equivalent, 0.06 M), sodium tert-butoxide (3 equivalents), and analkyl iodide from the table below (3 equivalents) in ethanol was heatedat reflux for 1-4 days. Additional alkyl iodide was added if necessary.The reaction mixture was allowed to cool to room temperature and aprecipitate was isolated by filtration, washed with water, and dried.The crude product was purified by IFC (silica gel, gradient elution withCMA in chloroform). In Example 579, the product was further purified byprecipitation from ethanol/water. In Examples 580 and 581, the productwas further purified by reverse phase chromatography (gradient elutionwith acetonitrile in water containing 0.5% formic acid). In allexamples, the final product was dried at 90° C. under vacuum.

Example 579: 1,2-Dibutyl-2H-pyrazolo[3,4-c]quinolin-4-amine was obtainedas a white powder, mp 143.0-145.0° C.

¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (dd, J=7.9, 1.1 Hz, 1H), 7.50 (dd,J=8.1, 1.1 Hz, 1H), 7.33 (td, J=7.2, 1.4 Hz, 1H), 7.22 (td, J=8.0, 1.3Hz, 1H), 6.59 (br s, 2H), 4.36 (t, J=7.3 Hz, 2H), 3.23 (t, J=8.1 Hz,2H), 1.91-1.85 (m, 2H), 1.69-1.63 (m, 2H), 1.49 (sextet, J=7.5 Hz, 2H),1.36 (sextet, J=7.6 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H), 0.93 (t, J=7.4 Hz,3H);

MS (APCI) m/z 297 (M+H)⁺;

Anal. calcd for C₁₈H₂₄N₄: C,72.94; H, 8.16; N, 18.90. Found: C, 72.70;H, 8.08; N, 19.05.

Example 580: The formic acid salt of1-butyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine was obtained as awhite powder, mp 164-166° C.

¹H NMR (700 MHz, DMSO-d₆) δ 8.17 (s, 0.8H), 7.90-7.89 (m, 1H), 7.50-7.49(m, 1H), 7.34-7.31 (m, 1H), 7.23-7.21 (m, 1H), 6.83 (br s, 2H), 4.34 (t,J=7 Hz, 2H), 3.23 (t, J=7.6 Hz, 2H), 1.95 (sextet, J=7.3 Hz, 2H), 1.67(pentet, J=7.9 Hz, 2H), 1.46 (sextet, J=7.5 Hz, 2H), 0.95 (t, J=7.3 Hz,3H), 0.92 (t, J=7.3 Hz, 3H);

¹³C NMR (175 MHz, DMSO) δ 163.34, 150.49, 143.04, 137.98, 135.33,125.69, 125.12, 121.74, 121.65, 119.48, 116.25, 50.76, 30.62, 24.57,23.53, 21.83, 13.66, 10.89;

MS (APCI) m/z 283 (M+H)⁺;

Anal. calcd for C₁₇H₂₂N₄.1.0 CH₂O₂.0.2 H₂O: C,65.12; H. 7.41; N, 16.87.Found: C, 64.73; H, 7.53; N, 16.92.

Example 581: The formic acid salt of1-butyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine was obtained as awhite powder, mp 202-203° C.

¹H NMR (500 MHz, DMSO-d₆) δ 8.17 (s, 0.8H), 7.92 (dd, J=7.9, 1.2 Hz,1H), 7.50 (dd, J=8.1, 1.1 Hz, 1H), 7.34 (td, J=7.1, 1.4 Hz, 1H), 7.23(td, J=7.9, 1.3 Hz, 1H), 6.83 (br s, 2H), 4.10 (s, 3H), 3.23 (t, J=7.6Hz, 2H), 1.67 (pentet, J=7.9 Hz, 2H), 1.46 (sextet, J=7.5 Hz, 2H), 0.94(t, J=7.3 Hz, 3H);

¹³C NMR (125 MHz, DMSO) δ 163.29, 150.38, 142.94, 138.15, 134.96,125.70, 125.05, 121.73, 121.54, 119.39, 116.46, 37.23, 30.10, 24.67,21.76, 13.62;

MS (APCI) m/z 255 (M+H)⁺;

Anal. calcd for C₁₅H₁₈N₄.0.8 CH₂O₂.0.02 H₂C: C,65.10; H, 6.79; N, 19.22.Found: C, 64.75; H, 6.74; N, 19.22.

Example Alkylating agent in Part B R 579 1-iodobutane —CH₂CH₂CH₂CH₃ 5801-iodopropane —CH₂CH₂CH₃ 581 iodomethane —CH₃

Examples 582 2-Isopropyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A poly(tetrafluoroethylene)-lined steel pressure vessel containing asolution of 2-benzyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 36, 0.8821 g, 3.06 mmol) in anhydroushydrogen bromide in acetic acid (10 mL) was heated in a 140° C. oven for17 hours. The vessel was allowed to cool to room temperature. A solidformed that was isolated by filtration and washed with water to yield1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine that was used in the nextstep.

Part B

The general method described in Part B of Examples 579-581 was used toconvert the material from Part A into2-isopropyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine, using2-iodopropane as the alkyl iodide. The purification method described forExample 579 was used to provide 0.0398 g of2-isopropyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a whitepowder, mp 221.0-222.0° C.

¹H NMR (500 MHz, DMSO-d₆) δ 8.02 (dd, J=7.9,1.2 Hz, 1H), 7.49 (dd,J=8.1, 1.0 Hz, 1H), 7.32 (td, J=7.1, 1.5 Hz, 1H), 7.20 (td, J=7.9, 1.3Hz, 1H), 6.52 (br s, 2H), 4.94 (septet, J=6.6 Hz, 1H), 2.84 (s, 3H),1.53 (d, J=6.6 Hz, 6H);

MS (APCI) m/z 241 (M+H)⁺;

Anal. calcd for C₁₄H₁₆N₄.0.15 H₂O: C,69.21; H, 6.76; N, 23.06. Found: C,68.81; H, 6.60; N, 22.85.

Example 583 4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butylacetate

1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3.8 g,12.5 mmol, prepared as described in Example 19) was combined withpotassium acetate (3.68 g, 37.5 mmol), sodium iodide (470 mg, 3.12mmol), and DMF (21 mL). The mixture was heated at 90° C. for 2 hours,allowed to cool to ambient temperature, diluted with water (100 mL),stirred for 20 minutes, and then filtered to remove a black solid. Thefiltrate was allowed to stand for 1 week at which time crystals hadformed. The crystals were isolated by filtration, purified bychromatography on a HORIZON HPFC system (25+M cartridge eluting withchloroform/CMA in a gradient from 100:0 to 70:30), and thenrecrystallized from acetonitrile to provide 55 mg of4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl acetate as atan crystalline solid, mp 128-129° C. MS (APCI) m/z 327 (M+H)⁺;

Anal. calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found: C,66.01; H, 6.89; N, 17.24.

Example 584N-[-3-(4-Amino-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)propyl]methanesulfonamide

Part A

Under a nitrogen atmosphere, a mixture sodium tert-butoxide (88.45 g,0.920 mol) and ethanol (625 mL) was stirred for 5 minutes and thencooled to 0° C. A solution of diethyl oxalate (119 mL, 0.877 mol) and6-chloro-2-pentanone (100 mL, 0.877 mol) in a minimal amount of ethanolwas added and a precipitate formed immediately. The reaction was stirredfor 5 minutes, then acetic acid (438 mL of 2 M) was added and a solutionwas obtained. Potassium acetate (129.0 g, 1.314 mol) was added and thereaction mixture was stirred for 3 minutes at which time it solidified.tert-Butylhydrazine oxalate hydrochloride (120.1 g, 0.964 mol) wasadded. The reaction was allowed to warm to ambient temperature withstirring overnight and then concentrated under reduced pressure. Theresidue was diluted with dichloromethane and water and the mixture wasadjusted to pH 11 with the addition of 2 M aqueous sodium carbonate. Theaqueous layer was extracted with dichloromethane; the combined organicswere dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide ethyl1-tert-butyl-5-(3-chloropropyl)-1H-pyrazole-3-carboxylate that was usedwithout purification.

Part B

The material from Part A was combined with 6 M sodium hydroxide (292 mL)and ethanol (219 mL), stirred at ambient temperature for 4 hours, andthen concentrated under reduced pressure. The residue was dissolved inwater. The solution was extracted with diethyl ether (2×100 mL) and thenacidified to pH 4 with 3 N hydrochloric acid. A precipitate formed; themixture was stirred for 30 minutes and then filtered. The isolated solidwas washed with water and then air dried for 48 hours to provide 65.9 gof 1-tert-butyl-5-(3-chloropropyl)-1H-pyrazole-3-carboxylic acid as atan solid.

Part C

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.63 g,45.0 mmol) was added to a solution of material from Part B (10 g, 40.9mmol) and 1-hydroxybenzotriazole hydrate (6.08 g, 45.0 mmol) in DMF (70mL). The solution was stirred for 30 minutes and then cooled to 0° C.Ammonium hydroxide (8.1 mL of 15 M, 123 mmol) was added and the solutionwas stirred at ambient temperature for 2 hours. The reaction mixture wasdiluted with water (200 mL) and then extracted with diethyl ether (4×150mL). The combined extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure to provide1-tert-butyl-5-(3-chloropropyl)-1H-pyrazole-3-carboxamide as a brownoil.

Part D

The material from Part C, triethylamine (17.1 mL, 123 mmol), anddichloromethane (136 mL) were combined and then cooled to 0° C.Trifluoroacetic anhydride (6.3 mL, 45 mmol) was added dropwise over aperiod of 1 minute. The reaction mixture was stirred for 2 hours andthen quenched with saturated ammonium chloride solution (30 mL). Thereaction mixture was diluted with water and then extracted withdichloromethane. The combined extracts were dried over sodium sulfate,filtered, and then concentrated under reduced pressure to provide1-tert-butyl-5-(3-chloropropyl)-1H-pyrazole-3-carbonitrile.

Part E

Bromine (2.5 mL, 49 mmol) was added in a single portion to a mixture ofthe material from Part D, potassium acetate (8.0 g, 82 mmol), and aceticacid (82 mL). The reaction mixture was stirred for 24 hours, quenchedwith sodium bisulfite, and then concentrated under reduced pressure. Theresidue was diluted with dichloromethane and water and the mixture wasadjusted to pH 11 with aqueous sodium carbonate. The aqueous layer wasextracted with dichloromethane. The combined organics were dried oversodium sulfate, filtered, and then concentrated under reduced pressureto provide a black oil. The oil was purified by column chromatography(silica gel eluting with 7:3 hexanes:ethyl acetate) to provide 7.5 g ofa dark yellow oil. Analysis by NMR indicated that the oil contained4-bromo-1-tert-butyl-5-(3-chloropropyl)-1H-pyrazole-3-carbonitrile 5 andstarting material in about a 9:1 ratio.

Part F

2-Aminophenylboronic acid hydrochloride (8.5 g, 49.2 mmol), potassiumphosphate (15.6 g, 73.8 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (563 mg, 0.615 mmol), andbis[(2-diphenylphosphino)phenyl]ether (397 mg, 0.738 mmol) were added toa solution of the material from Part E in toluene (153 mL) containingpowdered molecular sieves (1 g). Nitrogen was bubbled through thereaction mixture, and then the reaction was heated at 110° C. for 24hours. The mixture was cooled to ambient temperature and then filteredthrough a layer of silica gel (eluting with 3:2 chloroform/methanol).The filtrate was concentrated under reduced pressure and the residue wasdissolved in ethanol (120 mL). Hydrogen chloride (20 mL of a 4 Msolution in ethanol) was added to the resulting solution, and thereaction was heated at reflux for two hours and then allowed to cool toambient temperature. The solvent was removed under reduced pressure andthe residue was adjusted to pH 10 with the addition of 2 M aqueoussodium carbonate. The mixture was diluted with brine and extracted withdichloromethane. The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product waspurified by chromatography on a HORIZON HPFC system (65+M cartridge,eluting with chloroform/CMA in a gradient from 100:0 to 70:30). Thecleanest fractions were combined and concentrated under reducedpressure. The residue was recrystallized from acetonitrile to provide250 mg of off white crystals. The remaining fractions and the motherliquor from the recrystallization were combined and concentrated toprovide 2 g of2-tert-butyl-1-(3-chloropropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine as ayellow solid.

Part G

Methanesulfonamide (3.0 g, 31.5 mmol) was added to a chilled (0° C.)suspension of sodium hydride (60% dispersion in mineral oil, 1.2 g, 31.5mmol) in DMF (10 mL); the reaction was stirred at ambient temperaturefor five minutes. The yellow solid from Part F, DMF (4 mL) and sodiumiodide (235 mg, 1.57 mmol) were sequentially added. The reaction washeated at 90° C. for three hours, allowed to cool to ambienttemperature, and then poured into ice water (100 mL). The mixture wasstirred at ambient temperature for 1 hour at which time a precipitateformed. The solid was isolated by filtration and then dissolved in amixture of dichloromethane and chloroform. The solution was dried oversodium sulfate and then purified by chromatography on a HORIZON HPFCsystem (40+M cartridge eluting with chloroform/CMA in a gradient from100:0 to 70:30). The resulting solid was recrystallized fromacetonitrile to provide 80 mg ofN-[3-(4-amino-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)propyl]methanesulfonamideas gray crystals, mp 223-224° C. MS (APCI) m/z 376 (M+H)⁺; Anal. calcdfor C₁₈H₂₅N₅O₂S: C, 57.58; H, 6.71; N, 18.65 Found: C, 57.71; H, 7.00;N, 18.81.

Example 5851-(4-Amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

Part A

Under a nitrogen atmosphere, sodium tert-butoxide (54.1 g, 0.564 mol)and ethanol (187 mL) were combined at 0° C. The mixture was stirred atambient temperature for 30 minutes. A mixture of mesityl oxide (30 mL,0.26 mol) and diethyl oxalate (35.6 mL, 0.26 mol) in ethanol (40 mL) wasadded over a period of 1 minute. The reaction mixture was stirred for2.5 hours at ambient temperature and then cooled to 0° C. Acetic acid(131 mL) and methyl hydrazine (15.3 mL, 0.288 mol) were added. Thereaction was allowed to warm to ambient temperature with stirringovernight and then concentrated under reduced pressure. The residue wasdiluted with chloroform (500 mL) and water (1 L) and the mixture wasadjusted to pH 11 with the addition of 50% sodium hydroxide. The aqueouslayer was extracted with chloroform (3×250 mL); the combined organicswere dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide ethyl1-methyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylate as a blackoil that was used without purification.

Part B

The material from Part B was combined with 6 M sodium hydroxide (87 mL)and ethanol (655 mL), stirred at ambient temperature for 2 hours, andthen concentrated under reduced pressure. The residue was dissolved inwater and the solution acidified to pH 4 by the addition of 3 Nhydrochloric acid. A precipitate formed; the mixture was stirred for 30minutes and then filtered. The isolated solid was washed with water andthen air dried for 24 hours to provide 39 g of1-methyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylic acid as a tansolid.

Part C

The material from Part B was combined with dichloromethane (870 mL) anda drop of DMF. Oxalyl chloride (45.8 mL, 525 mmol) was added. Thereaction mixture was stirred at ambient temperature for 30 minutes andthen cooled to 0° C. Chilled (0° C.) ammonium hydroxide (250 mL of 15 M)was added in a single portion. The reaction mixture was stirred for 1hour and then extracted with chloroform. The combined extracts weredried and then concentrated under reduced pressure to provide 31.9 g of1-methyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide as a brownoil.

Part D

The material from Part C was combined with toluene (250 mL) and stirreduntil a solution was obtained. Phosphorous oxychloride (28.5 mL, 302mmol) was added and the reaction mixture was heated at reflux for 4hours. The toluene layer was poured into ice water; the mixture was madebasic by the addition of 2 N aqueous sodium carbonate and then extractedwith chloroform. The extracts were dried over sodium sulfate, filtered,and then concentrated under reduced pressure to provide1-methyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carbonitrile as a darkoil.

Part E

mCPBA (57 g of 50%) was added in a single portion to a solution of thematerial from Part D in dichloromethane (750 mL). The reaction mixturewas stirred at ambient temperature overnight and then filtered to removethe chlorobenzoic acid. The filter cake was rinsed with a small amountof dichloromethane. The filtrate was washed with aqueous saturatedsodium bicarbonate. The aqueous layer was extracted with dichloromethane(1×200 mL). The combined organics were dried over sodium sulfate,filtered, and then concentrated under reduced pressure to provide5-(3,3-dimethyloxiran-2-yl)-1-methyl-1H-pyrazole-3-carbonitrile.

Part F

Bromine (16.14 mL, 315 mmol) was added to a solution of the materialfrom Part E in acetic acid (300 mL) at 0° C. The red solution wasstirred at ambient temperature for 2 hours, and then saturated aqueoussodium bisulfite was added until the red color was gone. The mixture wasconcentrated under reduced pressure to remove the acetic acid. Theresidue was diluted with chloroform (100 mL) and the pH was adjustedwith 2 M aqueous sodium carbonate to pH 11. The cloudy mixture wasdiluted with water (50 mL) and extracted with chloroform (3×75 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to a cloudy oil. The oil wascombined with acetonitrile (300 mL) and aqueous hydrogen bromide (35 mLof 48%) and stirred for 1 hour. Aqueous saturated sodium bicarbonate wasadded until the mixture was basic. The resulting solution was dilutedwith water and then extracted with dichloromethane. The extracts weredried and concentrated under reduced pressure to provide a dark yellowoil. The oil was purified by chromatography on a HORIZON HPFC system(eluting with hexanes/ethyl acetate in a gradient from 9:1 to 1: 1) toprovide 10.5 g of crude4-bromo-5-(1-bromo-2-hydroxy-2-methylpropyl)-1-methyl-1H-pyrazole-3-carbonitrile.

Part G

Azobisisobutyronitrile (600 mg, 3.6 mmol) and tributyltin hydride (7.3mL, 27.3 mmol) were added to a mixture of portion of the material fromPart E (6.4 g, 18 mmol) and toluene (91 mL). After bubbling had ceased,the pale yellow solution was heated at 90° C. for 1 hour. Analysis byTLC indicated that starting material was still present. An additionalequivalent of tributyltin hydride was added and the reaction mixture washeated for an additional 30 minutes; this was repeated. The reactionmixture was purified by chromatography on a HORIZON HPFC system (65+Mcartridge eluting with hexanes/ethyl acetate in a gradient from allhexane to 1:1) to provide 2.7 g of4-bromo-5-(2-hydroxy-2-methylpropyl)-1-methyl-1H-pyrazole-3-carbonitrileas a colorless oil.

Part H

2-Aminophenylboronic acid hydrochloride (3.6 g, 20.8 mmol), potassiumphosphate (11.0 g, 52.0 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (238 mg, 0.26 mmol), andbis[(2-diphenylphosphino)phenyl]ether (167 mg, 0.312 mmol) were added toa solution of the material from Part G in toluene (65 mL) containingpowdered molecular sieves (1 g). Nitrogen was bubbled through thereaction mixture, and then the reaction was heated at 110° C. for 24hours. The mixture was cooled to ambient temperature and then filteredthrough a layer of silica gel (eluting with 3:2 chloroform/methanol).The filtrate was concentrated under reduced pressure and dissolved inethanol (52 mL). Hydrogen chloride (4.8 mL of a 4 M solution in ethanol)was added to the resulting solution, and the reaction was heated atreflux for two hours and allowed to cool to ambient temperature. Thesolvent was removed under reduced pressure and the residue was adjustedto pH 10 with the addition of 2 M aqueous sodium carbonate. The mixturewas diluted with brine and chloroform. A white solid that did notdissolve in either layer was isolated by filtration and thenrecrystallized from ethanol to provide 300 mg of1-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas gray crystals, mp 256-257° C. MS (APCI) m/z 271 (M+H)⁺; Anal. calcdfor C₁₅H₁₈N₄O: C, 66.65; H, 6.71; N, 20.73. Found: C, 66.51; H, 6.89; N,20.79.

Example 5861-(4-Amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

The mother liquor from Example 585 Part H was concentrated to provide 1g of1-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol.This material was combined with platinum oxide (750 mg) andtrifluoroacetic acid (25 mL) and shaken under hydrogen pressure on aParr apparatus for 2 days. The reaction mixture was filtered through alayer of CELITE filter agent and the filter cake was rinsed withdichloromethane. The filtrate was concentrated under reduced pressure.The residue was diluted with water (10 mL), the pH was adjusted to pH 12with 50% sodium hydroxide, and the mixture was extracted withdichloromethane. The extracts were dried over sodium sulfate and thenpurified by chromatography on a HORIZON HPFC system (40+M cartridgeeluting with a gradient of 0 to 30% CMA in chloroform). The resultingsolid was recrystallized from acetonitrile to provide 160 mg of1-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas tan crystals, mp 228-234° C. MS (APCI) m/z 275 (M+H)⁺; Anal. calcdfor C₁₅H₂₂N₄O: C, 65.67; H, 8.08; N, 20.42. Found: C, 65.53; H, 8.19; N,20.47.

Example 5871-(4-Amino-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

Using the method of Example 586,1-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol(100 mg, prepared as described in Example 62) was reduced and purifiedto provide 25 mg of1-(4-amino-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas a white powder, mp 202-204° C. ¹H NMR (500 MHz, DMSO-d₆) δ 5.96 (s,2H), 4.55 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 3.12 (s, 2H), 2.82 (m, 2H),2.57 (m, 2H), 1.72 (m, 4H), 1.39 (t, J=7.2 Hz, 3H), 1.34 (s, 6H); ¹³CNMR (75 MHz, DMSO-d₆) δ 6 149.11, 141.0, 135.20, 132.16, 123.77, 110.30,70.70, 45.56, 37.93, 32.09, 30.18, 25.10, 23.46, 23.15, 15.91;MS (APCI)m/z 289 (M+H)⁺; Anal. calcd for C₁₆H₂₄N₄O: C, 66.64; H, 8.39; N, 19.43.Found: C, 66.46; H, 8.58; N, 19.23.

Example 588 5-Butyl-2,3-dimethyl-2H-pyrazolo[3,4-c]pyridin-7-amine

Part A

Methylhydrazine (6.2 mL, 117 mmol) was added to a chilled (0° C.)solution of methyl pyruvic acetate (15.0 mL, 107 mmol) in acetic acid(210 mL). The reaction mixture was stirred for 1 hour and thenconcentrated under reduced pressure. The residue was diluted with water,made basic (pH 11) by the addition of aqueous saturated sodiumcarbonate, and then extracted with dichloromethane. The combinedextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to provide 14.6 g of ethyl1,5-dimethyl-1H-pyrazole-3-carboxylate as a dark oil.

Part B

The material from Part A (3.0 g, 17.8 mmol) was combined in a stainlesssteel reactor with 7 N ammonia in methanol (30 mL). The reaction wassealed and heated at 150° C. for 24 hours. The reaction mixture wasconcentrated under reduced pressure to provide 2.5 g of crude1,5-dimethyl-1H-pyrazole-3-carboxamide as a dark brown solid.

Part C

The material from Part B, triethylamine (7.5 mL, 54 mmol), anddichloromethane (60 mL) were combined and then cooled to 0° C.Trifluoroacetic anhydride (3.8 mL, 27 mmol) was added dropwise over aperiod of 1 minute. The reaction mixture was stirred for 2 hours andthen quenched with saturated ammonium chloride solution (30 mL). Thereaction mixture was diluted with water and then extracted withdichloromethane. The combined extracts were dried over sodium sulfate,filtered, and then concentrated under reduced pressure. The crudeproduct was purified by chromatography on a HORIZON HPFC system (40+Mcartridge, eluting with a gradient of 0 to 50% ethyl acetate in hexanes)to provide 1,5-dimethyl-1H-pyrazole-3-carbonitrile as a white solid.

Part D

A solution of iodine monochloride (3.9 g, 24.6 mmol) in dichloromethane(12 mL) was added to a mixture of material from Part C (1.5 g, 12.3mmol), dichloromethane (20 mL) and freshly ground potassium carbonate(3.2 g, 23 mmol). After 1 hour the reaction mixture was quenched withsodium bisulfite until all color was gone, diluted with water, and thenextracted with dichloromethane. The combined extracts were dried oversodium sulfate, filtered, and then concentrated under reduced pressure.The crude product was purified by chromatography on a HORIZON HPFCsystem (40+M cartridge, eluting with a gradient of 0 to 50% ethylacetate in hexanes) to provide 2.5 g of4-iodo-1,5-dimethyl-1H-pyrazole-3-carbonitrile as a white solid.

Part E

Under a nitrogen atmosphere, material from Part D (200 mg, 0.81 mmol),hexyne (0.18 mL, 1.6 mmol), copper(I) iodide (30 mg, 0.16 mmol),dichlorobis(triphenylphosphine)palladium(II) (57 mg, 0.081 mmol),triethylamine (0.24 mL, 2.4 mmol) and acetonitrile (4 mL) were combinedand then heated at reflux for 1 hour. The reaction mixture was cooled toambient temperature, diluted with 7:3 hexanes:ethyl acetate, and thenfiltered through a layer of CELITE filter agent. The filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on a HORIZON HPFC system (25+M cartridge, eluting with agradient of 0 to 50% ethyl acetate in hexanes) to provide 140 mg of4-(hex-1-ynyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile as a brown oil.

Part F

The material from Part E was combined in a stainless steel reactor with7 N ammonia in methanol (10 mL). The reaction was sealed and heated at150° C. for 58 hours. The reaction mixture was concentrated underreduced pressure to provide a brown oil. The oil was purified bychromatography on a HORIZON HPFC system (40+M cartridge, eluting with agradient of 0 to 20% CMA in chloroform) to provide a tan solid. Thismaterial was triturated with acetonitrile to provide 60 mg of5-butyl-2,3-dimethyl-2H-pyrazolo[3,4-c]pyridin-7-amine as a tan powder,mp 130-131° C. ¹H NMR (500 MHz, DMSO-d₆) δ 6.45 (s, 1H), 6.17 (s, 2H),4.00 (s, 3H), 2.46-2.49 (m, 5H), 1.16 (m, 2H), 1.30 (m, 2H), 0.89 (t,J=7.25 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 149.15, 146.42, 133.04,129.13, 122.17, 97.71, 36.10, 36.05, 30.44, 20.79, 12.80, 8.39;MS (APCI)m/z 219.2 (M+H)⁺; HRMS (ESI) calcd for C₁₂H₁₈N₄+H: 219.161, found219.1594. Anal. calcd for C₁₂H₁₈N₄.0.15 H₂O: C, 65.22; H, 8.35; N,25.35. Found: C, 65.52; H, 8.72; N, 25.64.

Example 589N-[4-(4-Amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]morpholine-4-carboxamide

Part A

A mixture of1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinoline-4-amine (2.8 g,8.6 mmol, prepared as described in Part F of Examples 454-488), platinumoxide, and trifluoroacetic acid was shaken under hydrogen pressure on aParr apparatus for 2 days. The reaction mixture was filtered through alayer of CELITE filter agent and the filter cake was rinsed withmethanol. The filtrate was concentrated under reduced pressure. Theresidue was diluted with water (10 mL), the pH was adjusted to pH 12with 50% sodium hydroxide, and the mixture was extracted withdichloromethane. The extracts were dried over sodium sulfate andconcentrated under reduce pressure. The residue was purified bychromatography on a HORIZON HPFC system (40+M cartridge eluting with agradient of 0 to 20% CMA in chloroform) to provide 2.0 g of1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amineas a yellow solid.

Part B

A mixture of1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine(385 mg, 1.31 mmol), potassium phthalimide (362 mg, 1.96 mmol), sodiumiodide (50 mg, 0.327 mmol), and DMF (2 mL) was heated at 90° C. for 4hours. The reaction mixture was cooled to ambient temperature and thendiluted with water (30 mL) while stirring in an ice bath. A precipitatewas isolated by filtration to obtain2-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dioneas a yellow solid.

Part C

The material from Part B was combined with hydrazine hydrate (0.3 mL,6.55 mmol) and ethanol (15 mL) and heated at reflux for 30 minutes. Thereaction mixture was chilled to 0° C. A precipitate was removed byfiltration and the filter cake was rinsed with ethanol. The filtrate waspurified by chromatography on a HORIZON HPFC system (25+M cartridgeeluting with a gradient of 0 to 40% CMA in chloroform) to provide 290 mgof1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine.

Part D

Under a nitrogen atmosphere, a mixture of the material from Part C,triethylamine (290 μL, 2.12 mmol), and dichloromethane (5 mL) was cooledto 0° C. 4-Morpholinecarbonyl chloride (124 μL, 1.06 mmol) was added in3 portions spaced 5 minutes apart. The reaction mixture was warmed toambient temperature and stirred for 1 hour. The reaction mixture wasquenched with saturated aqueous ammonium chloride, diluted with water,and then extracted with chloroform. The extract was dried over sodiumsulfate, filtered, and then purified by chromatography on a HORIZON HPFCsystem (25+M cartridge eluting with a gradient of 0 to 20% CMA inchloroform) to provide a clear oil. The oil was dissolved inacetonitrile. The acetonitrile was removed under reduced pressure andthe residue was placed under high vacuum with gentle heating to provideN-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]morpholine4-carboxamideas a white powder, mp 95° C. ¹H NMR (300 MHz, DMSO-d₆) δ 6.48 (t, J=5.3Hz, 1H), 5.99 (s, 2H), 4.00 (s, 3H), 3.51 (t, J=4.5 Hz, 4H), 3.22 (t,J=5.0 Hz, 4H), 3.07 (q, J=5.6 Hz, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.80 (bs,2H), 2.56 (bs, 2H), 1.74 (m, 4H) 1.51 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆)δ 156.51, 147.42, 139.56, 134.11, 133.45, 120.94, 108.33, 64.81, 42.72,39.56, 36.15, 30.41, 28.38, 26.42, 23.40, 23.23, 21.90,21.57; MS (APCI)m/z 387 (M+H)⁺; Anal. calcd for C₂₀H₃₀N₆O₂.H₂O: C, 59.39; H, 7.97; N,20.78. Found: C, 59.04; H, 7.89; N, 20.74.

Example 5901-(2-Amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Under a nitrogen atmosphere, 2-bromoethyl methyl ether (19.7 g, 142mmol) was added to a mixture of ethyl5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1H-pyrazole-3-carboxylate(40 g, 129 mmol, prepared according to the method of Example 64 Part Ausing hydrazine hydrate in lieu of propylhydrazine oxalate) and sodiumtert-butoxide (12.4 g, 129 mmol) in ethanol (128 mL). The reactionmixture was heated at reflux for 5 hours; an additional 0.2 equivalentsof both sodium tert-butoxide and 2-bromoethyl methyl ether were added,and the reaction mixture was heated at reflux for an additional 21hours. The reaction mixture was concentrated under reduced pressure andthe residue was partitioned between water and tert-butyl methyl ether.The aqueous layer was extracted with tert-butyl methyl ether (×3). Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide 46.0 g of IFC (65cartridge eluting with 1:1 tert-butyl methyl ether:hexanes) to provide apale yellow oil. This material was triturated with 40 mL of 1:1tert-butyl methyl ether:hexanes, seeded with product from an earlierrun, stirred until a white solid formed, and then concentrated underreduced pressure to provide 24.83 g of ethyl5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylateas a white solid, mp 92-93° C. MS (APCI) m/z 370 (M+H)⁺; Anal. Cacld forC₁₈H₃₁ N₃O₅: C, 58.52; H, 8.46; N, 11.37. Found: C, 58.65; H. 8.69; N,11.47.

Part B

Lithium hydroxide (17.1 g, 407 mmol) was added to a solution of ethyl5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate(37.6 g, 102 mmol) in methanol (141 mL) and water (47 mL). The reactionmixture was stirred for 2 days and then most of the methanol was removedunder reduced pressure. The aqueous residue was cooled in an ice bathand then combined with 1 N hydrochloric acid (350 mL) and tert-butylmethyl ether. The layers were separated. The volume of the organic layerwas reduced under vacuum and then diluted with hexanes. A precipitatewas isolated by filtration, washed with water, and suction dried toprovide 13.09 g of5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylicacid as a white solid. The aqueous layer was extracted with chloroformwhile maintaining the pH of the aqueous layer at pH 4-5 by the additionof 1 N hydrochloric acid. The chloroform extracts were combined, driedover sodium sulfate and magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was dissolved in tert-butyl methylether, diluted with hexanes, and then concentrated under reducedpressure. A white solid was isolated by filtration, washed with hexanes,and suction dried to provide an additional 21.8 g of product.

Part C

b 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.5 g,112 mmol) was added to a solution of5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylicacid (34.8 g, 102 mmol) and 1-hydroxybenzotriazole (15.2 g, 112 mmol) inDMF (174 mL) at ambient temperature. The mixture was stirred for 2.5hours until a solution formed and then it was cooled in an ice bath.Concentrated ammonium hydroxide (20.4 mL) was added and the reactionmixture was stirred for 30 minutes. Water (445 mL) was added and themixture was extracted with tert-butyl methyl ether (×12). The extractswere combined, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was concentrated twice from xyleneunder reduced pressure to provide 38 g of an oil. The oil was combinedwith 100 mL of 1:1 tert-butyl methyl ether:hexanes, warmed until asolution was obtained, and then let stand. An oil formed; the mixturewas concentrated under reduced pressure. The residue was dried undervacuum at 50° C. until a solid formed. The solid was slurried withhexanes, isolated by filtration, washed with hexanes, and suction driedto provide 31.3 g of tert-butyl2-[3-(aminocarbonyl)-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamateas a white solid.

Part D

Using the method of Example 64 Part D, tert-butyl2-[3-(aminocarbonyl)-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate(31.1 g) was dehydrated. The crude product was purified by IFC (65+Mcartridge eluting with a gradient of 50 to 60% ethyl acetate in hexanes)to provide 28.12 g of tert-butyl2-[3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamateas a white solid.

Part E

Bromine (19.5 g, 122 mmol) was added in a single portion to a solutionof tert-butyl2-[3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate(28.07 g, 87.1 mmol) and potassium acetate (12.8 g, 131 mmol) in aceticacid (174.2 mL). After 16 hours saturated aqueous sodium bisulfite wasadded until the reaction mixture was colorless. The acetic acid wasremoved under reduced pressure at about 30° C. The residue was madebasic with 2 M sodium carbonate and then extracted with tert-butylmethyl ether (×3). The extracts were combined, dried over magnesiumsulfate, and concentrated under reduced pressure. Analysis by HPLCindicated that the BOC group had been partially removed. The materialwas dissolved in dichloromethane (50 mL), combined with di-tert-butyldicarbonate, and stirred for 9 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was purified by IFC(65+M cartridge eluting with a gradient of 40 to 50% tert-butyl methylether in hexanes) to provide 32.1 g of tert-butyl2-[4-bromo-3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamateas a colorless, viscous resin.

Part F

Using the method of Example 64 Part F, tert-butyl2-[4-bromo-3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate(32.1 g, 80.0 mmol) was coupled with 2-aminophenylboronic acid. Thereaction mixture was partitioned between water and tert-butyl methylether. The aqueous layer was extracted with tert-butyl methyl ether(×2). The combined extracts were dried over magnesium sulfate, filtered,and concentrated to provide a brown oil. The oil was purified bychromatography on a HORIZON HPFC system (65+M cartridge eluting with agradient of 1 to 20% CMA in chloroform) to provide 11.4 g of an orangeresin. This material was purified IFC (65+M cartridge eluting with agradient of 35 to 55% ethyl acetate in hexanes) to provide 4.85 g oftert-butyl2-[4-(2-aminophenyl)-3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamateas an orange glassy resin.

Part G

Under a nitrogen atmosphere, acetyl chloride (100 mmol) was added to icecold ethanol (100 mL). The ice bath was removed; the mixture was stirredfor 3 hours and then combined with the material from Part F. Thereaction mixture was heated at reflux for 2 hours and then concentratedunder reduced pressure. The residue was combined with 2 M aqueous sodiumcarbonate (50 mL) and then extracted with chloroform (×4). The combinedextracts were dried over sodium sulfate, filtered, and concentrated toprovide 3.84 g of an orange solid. This material was purified by IFC(40+M cartridge eluting with a gradient of 25 to 55% CMA in chloroform)to provide 2.15 g of a white solid. This material was refluxed with 3:1ethyl acetate:hexanes (100 mL), chilled in an ice bath, isolated byfiltration, rinsed with a small amount of the solvent mixture, and thensuction dried to provide 1.94 g of a white solid. A portion (165 mg) ofthis material was recrystallized from acetonitrile (10 mL) to provide109 mg of1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 199-200 ° C. MS (APCI) m/z 314 (M+H)⁺; Anal. Calcdfor C₁₇H₂₃N₅O: C, 65.15; H, 7.40; N, 22.35. Found: C, 64.83; H, 7.38; N,22.70.

Example 591N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}isonicotinamide

Using the method of Example 68, isonicotinoyl chloride hydrochloride(710 mg, 4.00 mmol) was reacted with1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(500 mg, 1.60 mmol, prepared as described in Example 590). The crudeproduct was purified as described in Example 68 to provide 551 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}isonicotinamideas a white solid, mp 166-168° C. MS (ESI) m/z 419 (M+H)⁺; Anal. Calcdfor C₂₃H₂₆N₆O₂: C, 66.01; H, 6.26; N, 20.08. Found: C, 65.93; H, 6.41;N, 20.44.

Example 592N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide

Using the method of Example 66, methanesulfonyl chloride (399 mg, 3.48mmol) was reacted with1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(1.09 g, 3.48 mmol, prepared as described in Example 590). The crudeproduct was purified by IFC (40M cartridge eluting with a gradient of 15to 35% CMA in chloroform) to provide a white foam. The foam was refluxedwith 35% ethyl acetate in hexanes (50 mL), ethyl acetate was added untila free flowing white solid appeared, and then the mixture was cooled onice. The solid was isolated by filtration and dried to provide 809 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamideas a white solid, mp 211-213° C. MS (ESI) m/z 392 (M+H)⁺; Anal. Calcdfor C₁₈H₂₅N₅O₃S: C, 55.22; H, 6.44; N, 17.89. Found: C, 55.05; H, 6.38;N, 17.98.

Example 5934-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol

A solution of di(tert-butyl)1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(prepared as described in Parts A-C of Example 57, 0.507 g, 1.02 mmol)in 6 M HCl in ethanol (5 mL) was heated at 60° C. for 1.5 hours. Thesolution was allowed to cool to room temperature, and then wasconcentrated under reduced pressure to yield an oil. The oil wastriturated with ether to obtain a solid that was isolated by filtration.The solid was dissolved in methanol and the solution was adjusted toapproximately pH 14 with 50% aqueous sodium hydroxide. The solution wasconcentrated under reduced pressure and the crude product was purifiedby chromatography (silica gel, elution with 5% CMA in chloroform)followed by crystallization from hexanes/ethyl acetate to provide 0.084g of 4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol aswhite needles, mp 135.0-136.0° C.

¹H NMR (300 MHz, DMSO) δ 7.92 (d, J=7.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H),7.32 (t, J=7.0 Hz, 1H), 7.20 (t, J=7.0 Hz, 1H), 6.64 (s, 2H), 4.43 (t,J=5.0 Hz, 1H), 4.34 (t, J=7.2 Hz, 2H), 3.47 (q, J=5.8 Hz, 2H), 3.25 (t,J=7.5 Hz, 2H), 1.85-1.99 (m, 2H) 1.70-1.77 (m, 2H), 1.56-1.66 (m, 2H),0.92 (t, J=7.4 Hz, 3H);

MS (APCI) m/z 299 (M+H)⁺;

Anal. calcd for C₁₇H₂₂N₄O: C, 68.43; H, 7.43; N, 18.78. Found: C, 68.47;H, 7.62; N, 18.84.

Example 5944-(4-Amino-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol

4-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol (preparedas described in Example 593, 0.118 g, 0.396 mmol) was hydrogenated for1.8 days using the method described in Example 59. The catalyst wasremoved by filtration, and the filtrate was concentrated under reducedpressure to yield an oil that was dissolved in 6 M aqueous sodiumhydroxide (20 mL). The mixture was stirred for 1 day, then a white solidwas isolated by filtration, washed with water, and dried at 70° C. undervacuum to provide 0.719 g of4-(4-amino-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-olas a white powder, mp 194.0-200.0° C.

¹H NMR (300 MHz, DMSO) δ 5.95 (s, 2H), 4.41 (t, J=4.7 Hz, 1H), 4.22 (t,J=7.2 Hz, 2H), 3.44 (m, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.82 (s, 2H), 2.57(s, 2H), 1.82-1.91 (m, 2H), 1.74 (s, 4H), 1.49-1.59 (m, 4H), 0.89 (t,J=7.4 Hz, 3H);

MS (APCI) m/z 303 (M+H)⁺;

Anal. calcd for C₁₇H₂₆N₄O.0.2 H₂O.0.3 C₂F₃HO₂: C, 62.13; H, 7.91; N,16.47. Found: C, 62.10; H, 7.75; N, 16.40.

Example 5951-[3-(3-Methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A solution of acetaldoxime (1.00 g, 16.9 mmol) and N-chlorosuccinimide(2.26 g, 16.9 mmol) in DMF (50 mL) was heated at 50° C. for 1.5 hours.The solution was allowed to cool to room temperature and was partitionedbetween water and ethyl acetate. The layers were separated and theaqueous layer was extracted with ethyl acetate. The organic layers werecombined, dried over magnesium sulfate, filtered, and concentrated toyield 1.0545 g of α-chloroacetaldoxime as a clear colorless oil that wasused directly in the next step.

Part B

The oil from Part A (0.14 g, 1.5 mmol) was added to a solution ofdi(tert-butyl)1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(prepared as described in Parts A-E of Example 57, 0.590 g, 1.20 mmol)and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (10 mL). Thesolution was heated at 40° C. for 42 hours, during which time more ofthe material from Part A (0.357 g) was added. The solution was allowedto cool to room temperature, and then was diluted with dichloromethane.The solution was washed with an aqueous potassium carbonate solution,water, and brine, then was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bychromatography (silica gel, eluted with 40% ethyl acetate in hexanes) toprovide 0.4705 g of di(tert-butyl)1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a colorless oil.

Part C

A solution of di(tert-butyl)1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(0.471 g, 0.856 mmol) in 6 M HCl in ethanol (5 mL) was heated at 60° C.for 1 hour. The solution was allowed to cool to room temperature, thenwas concentrated under reduced pressure to yield an oil that wasdissolved in water (20 mL). The solution was adjusted to pH 12 with afew drops of 50% aqueous potassium hydroxide and then to pH 14 with 1 Maqueous potassium hydroxide. A precipitate formed that was isolated byfiltration and crystallized from ethyl acetate/hexanes. The crystalswere isolated by filtration and dried under vacuum at 70° C. to afford0.123 g1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas white needles, mp 183.0-184.0° C.

¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J=7.9 Hz, 1H), 7.70 (d, J=7.5 Hz,1H), 7.42 (t, J=7.1 Hz, 1H), 7.24-7.30 (m, 1H), 5.85 (s, 1H), 5.33 (s,2H), 4.26 (t, J=7.3 Hz, 2H), 3.25 (t, J=8.1 Hz, 2H), 2.91 (t, J=7.2 Hz,2H), 2.30 (s, 3H), 2.11-2.24 (m, 2H) 1.93-2.04 (m, 2H), 0.93 (t, J=7.4Hz, 3H);

MS (APCI) m/z 350 (M+H)⁺;

Anal. calcd for C₂₀H₂₃N₅O: C, 68.75; H, 6.63; N, 20.04. Found: C, 68.62;H, 6.80; N, 20.00.

Example 5961-[3-(3-Phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

α-Chlorobenzaldoxime was prepared according to the method described inPart A of Example 595 by reacting benzaldoxime (11.5 g, 94.9 mmol) inDMF (20 mL) with N-chlorosuccinimide (12.6 g, 94.9 mmol).α-Chlorobenzaldoxime (13.7 g, 93%) was obtained as a white solid.

Part B

α-Chlorobenzaldoxime (0.64 g, 4.1 mmol) was added to a solution ofdi(tert-butyl)1-pent4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(prepared as described in Parts A-E of Example 57, 1.36 g, 2.76 mmol)and triethylamine (0.60 mL, 4.14 mmol) in dichloromethane (10 mL). Thesolution was heated at 40° C. for 19 hours, during which time additionalα-chlorobenzaldoxime (0.65 g) was added. The reaction was worked up asdescribed in Part B of Example 595. The crude product was purified bychromatography (silica gel, sequential elution with 20% then 40% ethylacetate in hexanes) to provide 1.35 g of di(tert-butyl)1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a white solid.

Part C

A solution of the material from Part B in 6 M hydrochloric acid inethanol (10 mL) was heated at 60° C. for 45 minutes. The reactionmixture was concentrated under reduced pressure. The residue wasslurried with 1 N potassium hydroxide for 16 hours. The resulting solidwas isolated by filtration, rinsed with a 6:4 mixture of hexanes/ethylacetate, and dried at 80° for 3 hours to provide 0.7353 g of1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 176-178.0° C.

¹H NMR (300 MHz, CDCl₃) δ 7.77-7.83 (m, 3H), 7.71 (d, J=7.4 Hz, 1H),7.39-7.48 (m, 4H), 7.23-7.80 (m, 1H), 6.35 (s, 1H), 5.37 (s, 2H), 4.27(t, J=7.3 Hz, 2H), 3.2 (t, J=8.0 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.24(p, J=7.6 Hz, 2H), 1.99 (q, J=7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H);

MS (APCI) m/z 412 (M+H)⁺;

Anal. calcd for C₂₅H₂₅N₅O.0.6 H2O: C, 71.10; H, 6.25; N, 16.58. Found:C, 70.93; H, 6.36; N, 16.48.

Example 597 1-Pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

A solution of di(tert-butyl)1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(prepared as described in Parts A-E of Example 57, 0.400 g, 0.812 mmol)in 6 M HCl in ethanol (3 mL) was heated at 60° C. for 1.7 hours. Thesolution was allowed to cool to room temperature, and then wasconcentrated under reduced pressure to yield an oil. The oil was treatedwith 1 M aqueous potassium hydroxide to generate a white precipitate,which was isolated by filtration. The crude product was purified bychromatography (silica gel, gradient elution with 5-10% CMA inchloroform) followed by crystallization from hexanes/ethyl acetate toafford 0.061 g of1-pent4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as whitecrystals, mp 144.0-145.0° C.

¹H NMR (300 MHz, DMSO) δ 7.96 (d, J=7.4 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H),7.43 (t, J=7.5 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 5.41 (s, 2H), 4.34 (t,J=7.4 Hz, 2H) 3.35 (t, J=8.0 Hz, 2H), 2.35-2.41 (m, 2H), 2.14 (t, J=2.6Hz, 1H), 1.95-2.03 (m, 4H), 1.00 (t, J=7.4 Hz, 3H);

MS (APCI) m/z 293 (M+H)⁺;

Anal. calcd for C₁₈H₂₀N₄: C, 73.94; H, 6.89; N, 19.16. Found: C, 73.58;H, 6.90; N, 19.24.

Example 5981-[4-(3-Methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en4-yl)butyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A mixture of di(tert-butyl)1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(prepared as described in Part A of Example 57, 6.82 g, 13.2 mmol),sodium azide (1.74 g, 26.4 mmol), and sodium iodide (0.50 g, 3.30 mmol)in DMF (20 mL) was heated at 90° C. for 21 hours. The mixture wasallowed to cool to room temperature, then was poured into water (500 mL)and extracted with ethyl acetate. The organic layers were combined,washed with water and brine, dried over magnesium sulfate, filtered,concentrated under reduced pressure, and dried under vacuum to afford6.21 g of a brown solid that was used without further purification inthe next step.

Part B

A mixture of the material from Part A (6.21 g, 11.9 mmol),triphenylphosphine (4.7 g, 17.8 mmol), water (7 mL), and tetrahydrofuran(70 mL) was stirred at room temperature for 5 hours. The reactionmixture was concentrated under reduced pressure and the resulting oilwas dissolved in dichloromethane. The solution was washed with water andbrine, dried over sodium sulfate, and filtered. The filtrate was placedonto a column of silica gel and was eluted with ethyl acetate, followedby 5% methanol in dichloromethane, followed by 15% methanol indichloromethane. The appropriate fractions were combined andconcentrated to afford 3.37 g of di(tert-butyl)1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate.

Part C

A mixture of di(tert-butyl)1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(1.50 g, 3.01 mmol), cyclopentanone (1 mL, 11.31 mmol), and magnesiumsulfate in dichloromethane (9 mL) was stirred at room temperature for 1day. The mixture was filtered and the filtrate was concentrated underreduced pressure; and the residue was dissolved in dichloromethane (10mL). To the solution was added α-chloroacetaldoxime (prepared asdescribed in Part A of Example 595, 0.56 g, 6.03 mmol). The solution wascooled to 0° C. and triethylamine (1.00 mL, 7.54 mmol) was added. Themixture was allowed to warm to room temperature and was stirred for 1day. The mixture was transferred to a separatory funnel, washed with anaqueous solution of potassium carbonate, water, and brine, then driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by chromatography (silica gel, elutionwith 40% hexanes in ethyl acetate) to afford a 0.75 g of material thatwas used in the next step.

Part D

A solution of the material from Part C (0.75 g, 1.21 mmol) in 6 M HCl inethanol (6 mL) was heated at 60° C. for 2 hours. The solution wasallowed to cool to room temperature, then was concentrated under reducedpressure to yield an oil. The oil was treated with 6 M aqueous potassiumhydroxide. The aqueous solution was extracted with dichloromethaneseveral times. The organic layers were combined, washed with water andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by chromatography(silica gel, gradient elution with 5-15% CMA in chloroform) to afford0.131 g of1-[4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en4-yl)butyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 101.0-105.0° C.

¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.4 Hz,1H), 7.44 (t, J=7.5 Hz, 1H), 7.29 (t, J=7.0 Hz, 1H), 5.41 (s, 2H), 4.29(t, J=7.3 Hz, 2H), 3.25 (t, J=7.4 Hz, 2H), 3.03 (t, J=7.1 Hz, 2H), 2.02(q, J=7.3 Hz, 2H), 1.56-1.89 (m, 15H), 1.00 (t, J=7.4 Hz, 3H);

MS (APCI) m/z 421 (M+H)³⁰ ;

Anal. calcd for C₂₄H₃₂N₆O.0.8 H2O: C, 66.27; H, 7.79; N, 19.32. Found:C, 66.34; H, 7.62; N, 19.21.

Example 599N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide

Triethylamine (5 mmol) and acetyl chloride (4.0 mmol) were added to asolution of1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(496 mg, 1.60 mmol, prepared as described in Example 590) indichloromethane (20 mL). The reaction mixture was stirred for 30 minutesand then concentrated under reduced pressure. The residue was dissolvedin methanol (10 mL), and then combined with concentrated hydrochloricacid (2 mL). The mixture was heated at reflux for 2 hours, diluted with2 M aqueous sodium carbonate, and then concentrated under reducedpressure. The residue was extracted with chloroform. The extract wasdried over magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by IFC (RS-90 column, eluting with agradient of 20 to 35% CMA in chloroform) to provide 0.67 g of acolorless resin. This material was refluxed with 35% ethyl acetate inhexanes (50 mL), cooled to ambient temperature, and then the mixture wascooled on ice. The resulting solid was isolated by filtration, rinsedwith some of the solvent mix, and dried to provide 443 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}acetamideas a white solid, mp 170-171° C. MS (ESI) m/z 356 (M+H)⁺; Anal. Calcdfor C₁₉H₂₅N₅O₂: C, 64.20; H, 7.09; N, 19.70. Found: C, 63.89; H, 7.41;N,19.63.

Example 600N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}nicotinamide

Using the method of Example 68, nicotinoyl chloride hydrochloride (668mg, 4.75 mmol) was reacted with1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(470 mg, 1.5 mmol, prepared as described in Example 590). The crudeproduct was purified by IFC (silica gel eluting with a gradient of 10 to40% CMA in chloroform) to provide a pale yellow resin. The resin wasrefluxed with 35% ethyl acetate in hexanes (50 mL) and ethyl acetate (75mL) and cooled to ambient temperature with stirring. The resulting solidwas isolated by filtration, rinsed with 35% ethyl acetate in hexanes,and dried to provide 278 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}nicotinamideas a light beige solid, mp 212-214° C. MS (APCI) m/z 419 (M+H)⁺; Anal.Calcd for C₂₃H₂₆N₆O₂: C, 66.01; H, 6.26; N, 20.08. Found: C, 65.74; H,6.50; N, 20.09.

Example 601N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]4-fluorobenzamide

Using the general method of Example 68, except that the acid chloridewas added at 0° C.,1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 770 mg, 2.59 mmol) was reactedwith 4-fluorobenzoyl chloride (1.03 g, 6.48 mmol) to provide 2.1 g ofcrude product as pale yellow resin. This material was purified by IFC(silica gel eluting with a gradient of 5 to 20% CMA in chloroform) toprovide about 1 g of a white foam. The foam was stirred with 35% ethylacetate in hexanes. The resulting solid was isolated by filtration,rinsed with the same solvent mix, and then dried to provide 503 mg of awhite solid (A). The filtrate was concentrated under reduced pressure toprovide a white solid. This material was dissolved in dichloromethane,precipitated with hexanes, isolated by filtration, rinsed with hexanes,and dried to provide 340 mg of a white solid (B). White solids A and Bwere combined, refluxed in 20% ethyl acetate in hexanes, cooled toambient temperature, and then in an ice bath. The resulting solid wasisolated by filtration, rinsed with 20% ethyl acetate in hexanes, anddried to provide 706 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-4-fluorobenzamideas a white solid, mp 168-169° C. MS (APCI) m/z 420 (M+H)⁺; Anal. Calcdfor C₂₄H₂₆FN₅O: C, 68.72; H, 6.25; N, 16.69. Found: C, 68.69; H, 6.15;N, 16.90.

Example 602N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-3,4-difluorobenzamide

Using the method of Example 601,1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 770 mg, 2.59 mmol) was reactedwith 3,4-difluorobenzoyl chloride (1.14 g, 6.48 mmol). The crude productwas purified as described in Example 601 to provide 896 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-3,4-difluorobenzamideas a white solid, mp 165-166° C. MS (APCI) m/z 438 (M+H)⁺; Anal. Calcdfor C₂₄H₂₅F₂N₅O: C, 65.89; H, 5.76; N, 16.01. Found: C, 65.84; H, 5.58;N, 15.92.

Example 603N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]isonicotinamide

Using the method of Example 68,1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 770 mg, 2.59 mmol) was reactedwith isonicotinoyl chloride hydrochloride (1.15 mg, 6.48 mmol). Thecrude product was purified as described in Example 68 to provide 708 mgofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]isonicotinamideas an off-white solid, mp 148-150° C. MS (APCI) m/z 403 (M+H)⁺; Anal.Cacld for C₂₃H₂₆N₆O: C, 68.63; H, 6.51; N, 20.88. Found: C, 68.30; H,6.49; N, 20.92.

Example 604N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-3,4-difluorobenzamide

Using the general method of Example 599,1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(0.52 g, 1.66 mmol, prepared as described in Example 590) was reactedwith 3,4-difluorobenzoyl chloride. The crude product was purified asdescribed in Example 599 to provide 382 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-3,4-difluorobenzamideas a white solid, mp 199-200° C. MS (ESI) m/z 454 (M+H)⁺; Anal. Calcdfor C₂₄H₂₅F₂N₅O₂: C, 63.57; H, 5.56; N, 15.44. Found: C, 63.37; H, 5.50;N, 15.58.

Example 605N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]propionamide

Using the method of Example 68,1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 595 mg, 2.00 mmol) was reactedwith propionyl chloride (463 mg, 5.00 mmol). The crude product waspurified by IFC (silica gel eluting with a gradient of 15 to 25% CMA inchloroform) followed by recrystallization from ethyl acetate/hexanes toprovide 545 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]propionamideas a white solid, mp 158-159° C. MS (APCI) m/z 354 (M+H)⁺; Anal. Calcdfor C₂₀H₂₇N₅O: C, 67.96; H, 7.70; N, 19.81. Found: C, 67.80; H, 8.08; N,19.77

Example 606N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}propionamide

Using the general method of Example 599,1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(500 mg, 1.60 mmol, prepared as described in Example 590) was reactedwith propionyl chloride (370 mg, 4.00 mmol). The crude product waspurified by IFC (silica gel eluting with a gradient of 15 to 50% CMA inchloroform) followed by recrystallization from ethyl acetate/hexanes toprovide 434 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}propionamideas a white solid, mp 157-158° C. MS (APCI) m/z 370 (M+H)⁺; Anal. Calcdfor C₂₀H₂₇N₅O₂: C, 65.02; H, 7.37; N, 18.96. Found: C, 64.79; H, 7.58;N, 18.94.

Example 607N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-4-fluorobenzamide

Using the general method of Example 599,1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-Z4-amine(500 mg, 1.60 mmol, prepared as described in Example 590) was reactedwith 4-fluorobenzoyl chloride (634 mg, 4.00 mmol). The crude product waspurified by IFC (silica gel eluting with a gradient of 5 to 20% CMA inchloroform) followed by recrystallization from ethyl acetate/hexanes toprovide 551 mg ofN-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-4-fluorobenzamideas a white solid, mp 187-189° C. MS (ESI) m/z 436 (M+H)⁺; Anal. Calcdfor C₂₄H26FN₅O₂: C, 66.19; H, 6.02; N, 16.08. Found: C, 65.92; H, 5.93;N, 15.87.

Example 608N-{2-[4-Amino-2-(2-hydroxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide

Boron tribromide (1 M in dichloromethane, 2.15 mL, 2.15 mmol) was addedover a period of 2 minutes to a chilled (0° C.) slurry ofN-{2-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide(337 mg, 0.861 mmol, prepared as described in Example 592) indichloromethane (10 mL). The reaction mixture was stirred for 14 hoursand then concentrated under reduced pressure. The residue was combinedwith 6 M hydrochloric acid and stirred for 3 hours. The reaction mixturewas diluted with 2 M aqueous sodium carbonate. The resulting precipitatewas isolated by filtration and rinsed with water and chloroform. Theprecipitate was combined with the chloroform layer and concentratedunder reduced pressure. The residue was purified by IFC (silica geleluting with a gradient of CMA in chloroform) followed byrecrystallization from ethyl acetate/hexanes/acetonitrile to provide 184mg ofN-{2-[4-amino-2-(2-hydroxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamideas a white solid, mp 203-204° C. MS (ESI) m/z 378 (M+H)⁺; Anal. Calcdfor C₂₇H₂₃N₅O₃S: C, 54.09; H, 6.14; N, 18.55. Found: C, 54.11; H, 5.97;N, 18.42.

Example 609 2-(4-Amino-1-methyl-2H-pyrazolo[3,4-c]quinolin-2-yl)ethanol

Part A

A solution of 2-hydroxyethylhydrazine (15.2 g, 200 mmol) in ethanol (50mL) was added over a period of 30 minutes to a solution of ethyl2,4-dioxopentanoate (31.6 g, 200 mmol) in ethanol (200 mL). The reactionmixture was stirred for an additional 20 minutes and then concentratedunder reduced pressure to provide 45 g of ethyl1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxylate a light brown oil.A portion (31.1 g) of this material was combined in a Parr vessel withmethanol (25 mL) and concentrated ammonium hydroxide (25 mL). The vesselwas sealed and the mixture was heated for 12 hours. The reaction mixturewas concentrated under reduced pressure to provide a brown resin. Theresin was stirred with a mixture of chloroform and methanol until asolid appeared. The solid was isolated by filtration and thenrecrystallized from isopropanol to provide 7.01 g of1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide as a white solid.The rest of the ester was purified by IFC (silica gel eluting with agradient of 50 to 100% ethyl acetate in hexanes) to provide 6.6 g of apale yellow oil. This material was dissolved in concentrated ammoniumhydroxide (25 mL) and allowed to stand at ambient temperature for 48hours. A precipitate was isolated by filtration, rinsed with water, anddried to provide 3.74 g of1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide as white needles,mp 170-172° C. Anal. Calcd for C₇H₁₁N₃O₂: C, 49.70; H, 6.55; N, 24.84.Found C, 49.59; H, 6.65; N, 24.92.

Part B

Under a nitrogen atmosphere, triethylamine (17.9 g, 177 mmol) was addedto a slurry of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide(7.0 g, 41.4 mmol) in dichloromethane (70 mL). The mixture was cooled inan ice bath and then a solution of trifluoroacetic anhydride (15.6 g,74.2 mmol) in dichloromethane (70 mL) was added over a period of 10minutes. All of the solids dissolved to provide a cloudy solution. After1 hour additional triethylamine (70.6 mmol) was added and the reactionmixture was cooled in an ice bath. Trifluoroacetic anhydride (35.3 mmol)was added neat over a period of 5 minutes. The reaction mixture wasstirred for 10 minutes then the ice bath was removed and the reactionmixture was stirred for 30 minutes. The reaction mixture was dilutedwith 2 M aqueous sodium carbonate (100 mL) and water (100 mL) thenextracted with chloroform (×3). The extracts were combined, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toprovide 11.5 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carbonitrilea brown oil.

Part C

Potassium acetate (5.2 g, 53 mmol) and bromine (7.9 g, 49.4 mmol) wereadded sequentially to a solution of the material from Part B in aceticacid (70 mL). The reaction mixture was stirred for 20 hours and thenquenched with aqueous saturated sodium bisulfite. The acetic acid wasremoved under reduced pressure. The residue was made basic with 2 Maqueous sodium carbonate and then extracted with chloroform (×3). Theextracts were combined, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide 11 g of a brown oil. Theoil was purified by IFC (silica gel eluting with a gradient of 50 to 75%ethyl acetate in hexanes) to provide 3.48 g of4-bromo-1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carbonitrile as ayellow oil.

Part D

2 M aqueous sodium carbonate (11.8 mL), 2-aminophenylboronic acidhydrochloride (2.04 g, 11.8 mmol), water (2.76 mL), triphenylphosphine(186 mg, 0.709 mmol), and palladium (II) acetate (53 mg, 0.236 mmol)were added sequentially to a solution of4-bromo-1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carbonitrile (1.812 g,7.88 mmol) in propanol (13.8 mL) in a 100 mL round bottom flask. Theflask was evacuated then filled with nitrogen. The reaction mixture washeated at reflux for 22 hours. The reaction mixture was extracted withchloroform (×4). The extracts were combined, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to provide ayellow oil. The oil was refluxed with tert-butyl methyl ether to provideabout 1 g of a gummy solid. This material was purified by IFC (silicagel eluting with a gradient of 30 to 75% CMA in chloroform) to provideabout 400 mg of a pale yellow solid. This material was recrystallizedfrom acetonitrile (50 mL) to provide 187 mg of2-(4-amino-1-methyl-2H-pyrazolo[3,4-c]quinolin-2-yl)ethanol as a whitesolid, mp 226-228° C. MS (APCI) m/z 243 (M+H)⁺; Anal. Calcd forC₁₃H₁₄N₄O: C, 64.45; H, 5.82; N, 23.12. Found: C, 64.31; H, 6.01; N,23.18.

Example 6102-Ethyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]-1,7-naphthyridin-4-amine

Propanol (5 mL) and 2 M hydrochloric acid (1.6 mL) were added to3-[(tert-butoxycarbonyl)amino]pyridin-4-ylboronic acid (1.04 g, 4.37mmol), prepared as described in Example 15 using tert-butylN-(3-pyridyl)carbamate in lieu of tert-butyl N-(2-pyridyl)carbamate. Themixture was refluxed for 30 minutes to remove the BOC group. Solidsodium carbonate (710 mg, 6.7 mol),4-bromo-1-ethyl-5-(2,2-dimethylpropyl)-1H-pyrazole-3-carbonitrile (786mg, 2.91 mmol), prepared as described in Example 38,bis[(2-diphenylphosphino)phenyl]ether (47 mg, 0.087 mmol), and palladium(II) acetate (19.5 mg, 0.087 mmol) were added. The flask was evacuatedand then filled with nitrogen three times. The reaction mixture washeated at reflux for 18 hours and then partitioned between water andchloroform. The aqueous layer was extracted with chloroform (×3). Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide a yellow oil. The oil waspurified by IFC (silica gel eluting with a gradient of 2 to 45% CMA inchloroform) to provide 180 mg of a yellow resin. This material waspurified by IFC (silica gel eluting with 15% CMA in chloroform) toprovide 120 mg of product. This material was refluxed in 35% ethylacetate in hexanes (15 mL) then diluted with hexanes (15 mL) andchilled. The resulting solid was isolated by filtration and dried toprovide 54 mg of a white solid. Analysis by ¹H NMR and IR indicated thepresence of the biaryl intermediate and a nitrile group. Acetyl chloride(393 mg) and anhydrous ethanol (5 mL) were combined and stirred for 30minutes. The white solid was added and the mixture was refluxed undernitrogen for 5 hours. The reaction mixture was allowed to stand for 48hours; then it was diluted with 2 M aqueous sodium carbonate andconcentrated under reduced pressure. The residue was extracted withchloroform (x 4). The combined extracts were dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to provide awhite solid. This material was dissolved in a minimal amount ofdichloromethane and then precipitated with hexanes. The solid wasisolated by filtration and dried to provide 28 mg of2-ethyl-1-(2,2-dimethylpropyl)-2H-pyrazolo[3,4-c]-1,7-naphthyridin4-amineas a white solid, mp>260° C. HRMS (ESI) Cacld for C₁₆H₂₁N₅+H 284.1875,found 284.1860.

Example 6111-(3-Benzenesulfonylpropyl)-2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Sodium metal (23 mg, 1 mmol) was added to 25 mL of methanol. After thesodium metal was consumed, methyl acetoacetate (1.16 g, 10 mmol) wasadded to the mixture and stirred for 15 minutes. A solution of phenylvinyl sulfone (1.68 g, 10 mmol) was added dropwise to the solution andmaintained for several hours. The slightly yellow solution wasconcentrated under reduced pressure, and the residue was diluted withethyl acetate and washed with saturated aqueous ammonium chloride. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated to afford a clear oil. The material was purified viaflash column chromatography on silica gel (eluting with hexane:ethylacetate in a gradient from 3:2 to 2:3) to afford 1.40 g of ethyl2-(2-benzenesulfonylethyl)-3-oxo-butyrate.

Part B

Hydrochloric acid was added (150 mL of 3 N) to a solution of ethyl2-(2-benzenesulfonylethyl)-3-oxo-butyrate (21.7 g, 76.3 mmol) in 100 mLof ethanol and heated to reflux overnight. The reaction was cooled toambient temperature and the mixture was concentrated under reducedpressure. The residue was extracted with several portions of ethylacetate, and the combined organic layers were washed with saturatedaqueous sodium bicarbonate, washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to afford16.8 g of 5-benzenesulfonylpentan-2-one as a yellow oil.

Part C

Sodium tert-butoxide (15.4 g, 160 mmol) was combined with ethanol (53mL) and allowed to stir for 30 minutes. 5-Benzenesulfonylpentan-2-one(16.8 g, 74.2 mmol) and diethyl oxalate (10.1 mL, 74.2 mmol) were addedto the reaction mixture in 20 mL of ethanol via an addition funnel. Thereaction was maintained for 1 hour and the solution changed in colorfrom orange to red. Potassium acetate (10.9 g, 111 mmol) was added tothe reaction mixture, followed by addition of acetic acid (37 mL, 2M).The reaction mixture was then cooled to 0° C. and butyl hydrazineoxalate (13.2 g, 74.2 mmol) was added. The resultant slurry was stirredfor 2 hours and turned yellow. The reaction mixture was concentratedunder reduced pressure, diluted with water, and the pH of the mixturewas adjusted to 11 by addition of sodium carbonate. The reaction mixturewas extracted with chloroform while adding additional water to minimizeelusion formation. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure to afford a red oil. The material was purified by columnchromatography on silica gel (eluting with hexane:ethyl acetate in agradient from 3:1 to 1:1) to yield 13.3 g of ethyl5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylate as anorange oil.

Part D

Sodium hydroxide (12 mL, 6M) was added to a solution of ethyl5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylate (13.3 g,35.1 mmol) in 100 mL of ethanol and heated to reflux overnight. Thereaction mixture was concentrated under reduced pressure and the residuewas diluted with 100 mL of water. The aqueous layer was extracted withseveral portions of ethyl acetate. The pH of the aqueous layer wasadjusted to approximately 2-3 with aqueous hydrochloric acid and wasthen extracted with several portions of ethyl acetate. The combinedorganic layers originating from extraction of the aqueous layer werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated to afford 10.5 g of5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylic acid.

Part E

Oxalyl chloride (7.8 mL, 90.0 mmol) was added slowly via syringe to asolution of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxylicacid (10.5 g, 30.0 mmol) in 100 mL of dichloromethane containing onedrop of DMF. After 2 hours of stirring, saturated ammonium chloride (100mL) was added to the reaction mixture and the reaction was maintainedfor 1 hour. The reaction mixture was concentrated under reducedpressure, diluted with dichloromethane and washed with water. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to afford 10.4 g of5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxamide.

Part F

Phosphorus oxychloride (25 mL) was added to5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxamide (10.4 g,30.0 mmol) and heated to 90° C. for 2.5 hours. The reaction mixture wasthen cooled to ambient temperature and poured into ice water cooled byan ice bath. Additional ice was added to the reaction mixture and the pHof the mixture was adjusted to 8-9 by addition of 30% saturated aqueousammonium hydroxide. The mixture was extracted with ethyl acetate and thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to afford 8.60 g of5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile.

Part G

Potassium acetate (3.82 g, 38.9 mmol) was added to a solution of5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile (8.60 g,25.9 mmol) in 50 mL of acetic acid. The reaction mixture was stirreduntil all solids had dissolved, followed by dropwise addition of bromine(1.33 mL, 25.9 mmol) over 5 minutes. The resultant red solution wasstirred for 5 hours and aqueous sodium thiosulfate was added to quenchexcess bromine. The reaction mixture was concentrated under reducedpressure and the residue was diluted with 200 mL of water. The pH of themixture was adjusted to 8-9 by slow addition of solid sodium carbonatefollowed by extraction with several portions of ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to afford anorange oil. Purification via flash column chromatography on silica gel(eluting with hexane:ethyl acetate in a gradient from 3:1 to 1:1)afforded 4.80 g of5-(3-benzenesulfonylpropyl)-4-bromo-1-butyl-1H-pyrazole-3-carbonitrileas a colorless oil that crystallized upon standing.

Part H

2-Aminophenyl boronic acid hydrochloride (693 mg, 4.00 mmol) andpotassium phosphate tribasic (2.12 g, 10.0 mmol) were added sequentiallyto a solution of5-(3-benzenesulfonylpropyl)4-bromo-1-butyl-1H-pyrazole-3-carbonitrile(550 mg, 1.30 mmol) in 15 mL of toluene in a pressure tube. Nitrogen wasbubbled through the resultant slurry for 15 minutes.Tris(dibenzylideneacetone)dipalladium(0) (104 mg, 0.10 mmol),bis[(2-diphenylphosphino)phenyl]ether (65 mg, 0.12 mmol), and 4 angstrommolecular sieves were then added to the reaction mixture. The pressuretube was sealed and heated in a 110° C. oil bath. After 20 hours, thereaction mixture was cooled to ambient temperature, diluted with ethylacetate and filtered through CELITE filter aid. The filtrate was dilutedwith ethyl acetate and washed with saturated aqueous sodium bicarbonate.The aqueous layer was extracted with additional ethyl acetate and thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to an orange oil. Purification viaflash column chromatography on silica gel (eluting with hexane:ethylacetate in a gradient from 2:1 to 2:3) afforded 550 mg of4-(2-aminophenyl)-5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrileas a thick pale yellow oil.

Part I

Hydrochloric acid (0.98 mL, 3.90 mmol) in ethanol was added dropwise toa solution of4-(2-aminophenyl)-5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile(550 mg, 1.30 mmol) in 10 mL of ethanol. The resultant solution wasstirred for 2 hours, concentrated under reduced pressure, and dilutedwith water. The pH of the mixture was adjusted to 8-9 by slow additionof solid sodium carbonate. The aqueous layer was extracted with severalportions of dichloromethane. The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to afford a pale yellow solid. The material waspurified via flash column chromatography on silica gel (eluting with a97:3 mixture of dichloromethane/methanol) to afford 350 mg of1-(3-benzenesulfonylpropyl)-2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white crystalline solid, mp 206-207° C. ¹H NMR (300 MHz, CDCl₃) δ7.87 (d, J=6.9 Hz, 2H), 7.77 (dd, J=1.2, 8.1 Hz, 1H), 7.69 (dd, J=0.9,8.1 Hz, 1H), 7.63 (m, 1H), 7.53 (m, 2H), 5.37 (br s, 2H), 4.35 (app t,J=7.2 Hz, 2H), 3.45 (m, 2H), 3.22 (t, J=7.1 Hz, 2H), 2.23 (m, 2H), 1.94(m, 2H), 1.40 (qd, J=7.2, 14.6 Hz, 2H), 0.98 (t. J=7.3 Hz, 3H); MS(APCI) m/z 423 (M+H⁺); Anal. calcd for C₂₃H₂₆N₄O₂S: C, 65.38; H, 6.20;N, 13.26. Found: C, 65.40; H, 6.01; N, 13.26.

Example 6121-(4-Methanesulfonylbutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

2-Aminophenyl boronic acid hydrochloride (9.10 mg, 26.3 mmol) andfreshly ground potassium phosphate tribasic (27.8 g, 131 mmol) wereadded sequentially to a solution of4-bromo-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile (8.00 g,26.3 mmol), prepared as described in Example 46, in 100 mL of toluene ina pressure tube. Nitrogen was bubbled through the resultant slurry for15 minutes. Tris(dibenzylideneacetone)dipalladium(0) (1.36 g, 1.31mmol), bis[(2-diphenylphosphino)phenyl]ether (851 mg, 1.58 mmol), and 4angstrom molecular sieves were then added to the reaction mixture. Thepressure tube was sealed and heated in a 110° C. oil bath. After 24hours, the reaction mixture was cooled to ambient temperature, dilutedwith ethyl acetate and filtered through CELITE filter aid. The filtratewas diluted with ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The aqueous layer was extracted with additional ethylacetate and the combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated to a red oil.Purification via flash column chromatography on silica gel (eluting with2:1 hexane:ethyl acetate) afforded 7.60 g of4-(2-aminophenyl)-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrileas a red oil.

Part B

Hydrochloric acid (18 mL, 71.0 mmol) in ethanol was added dropwise to asolution of4-(2-aminophenyl)-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile(7.50g, 23.7 mmol) in 150 mL of ethanol. The resultant solution washeated to reflux overnight, concentrated under reduced pressure, anddiluted with water. The pH of the mixture was adjusted to 9-10 by slowaddition of solid sodium carbonate. The aqueous layer was extracted withseveral portions of dichloromethane. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to afford a reddish solid. Thematerial was purified via flash column chromatography on silica gel(eluting with a 96:4 mixture of dichloromethane/methanol) to afford 4.78g of 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part C

Sodium thiomethoxide (0.3 g, 3.79 mmol) was added to a solution of1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.0 g,3.16 mmol) in 15 mL of DMF and heated for 3 hours at 80° C. The reactionmixture was allowed to cool to ambient temperature, diluted withdichloromethane, and washed with water. The aqueous layer was extractedwith several additional portions of dichloromethane and the combinedorganic layers were washed with water, washed with brine, dried overmagnesium sulfate, and concentrated to afford 1.04 g of1-(4-methylthiobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as ayellow solid.

Part D

3-Chloroperoxybenozic acid (mCPBA) (75% pure, 1.60 g, 6.97 mmol, 2.2 eq)was added portion wise to a solution of1-(4-methylthiobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.04g, 3.16 mmol) in 50 mL of chloroform over several minutes. The resultingreaction mixture was stirred at ambient temperature for 2 hours andbecame darker red in color. The mixture was then washed with saturatedaqueous sodium bicarbonate, the layers were separated, and the aqueouslayer was further extracted with dichloromethane. The combined organiclayers were washed with brine, dried over magnesium sulfate, filtered,and concentrated under reduced pressure to afford a dark oil. Thematerial was purified via flash column chromatography on silica gel(eluting with dichloromethane/methanol in a gradient from 97:3 to 93:7),diluted with acetonitrile, washed with saturated aqueous sodiumbicarbonate, and purified a second time via flash column chromatographyon silica gel (eluting with dichloromethane/methanol in a gradient from97:3 to 93:7). The product was recrystallized from acetonitrile toafford 960 mg of1-(4-methanesulfonylbutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a yellow crystalline solid, mp 155-157° C. ¹H NMR (300 MHz, CDCl₃) 67.85 (m, 1H), 7.73 (dd, J=1.2, 8.1 Hz, 1H), 7.46 (dt, J=1.2, 6.9 Hz,1H), 7.32 (dt, J=1.2, 7.5 Hz, 1H), 5.54 (br s, 2H), 4.31 (t, J=7.2 Hz,2H), 3.29 (t, J=7.5 Hz, 2H), 3.07 (t, J=7.5 Hz, 2H), 2.90 (s, 3H),2.12-1.93 (m, 6H), 1.02 (t, J=7.2 Hz, 3H); MS (APCI) m/z 361 (M+H⁺);Anal. calcd for C₁₈H₂₄N₄O₂S (containing 0.5 CH₃CN): C, 59.90; H, 6.75;N, 16.54. Found: C, 59.89; H, 6.83; N, 16.77.

Example 613 Alternative preparation of1-(4-Aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Using the method of Example 593, the protecting groups were removed fromdi(tert-butyl)1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(0.368 mg), prepared as described in Example 598. The crude product waspurified by column chromatography (silica gel eluting withchloroform/CMA in a gradient of 95:5 to 8:2) to provide 0.0993 g of1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a whitepowder, mp 156.0-157.0° C. ¹H NMR (500 MHz, DMSO-d6) δ 7.90 (d, J=7.9Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.19 (t, J=8.1Hz, 1H), 6.62 (s, 2H), 4.34 (t, J=7.3 Hz, 2H), 3.23 (t, J=7.8 Hz, 2H),2.69 (t, J=6.9 Hz, 2H), 1.92 (t, J=7.3 Hz, 2H), 1.67-1.71 (m, 2H),1.49-1.57 (m, 4H), 0.92 (t, J=7.4 Hz, 3H);

MS (APCI) m/z 298 (M+H)⁺; Anal. calcd for C₁₇H₂₃N₅.0.3 H₂O: C, 67.43; H,7.86; N, 23.13. Found: C, 67.61; H, 7.98; N, 23.20.

Example 6142-Propyl-1-[4-(3,5,5-trimethyl-1,2,4-oxadiazol4(5H)-yl)butyl]-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Using the general method of Example 598 Part C, di(tert-butyl)1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(1.50 g, 3.01 mmol), prepared as described in Example 598, was reactedwith acetone to form an imine intermediate and the imine was treatedwith α-chloroacetaldoxime. The crude product was purified bychromatography (silica gel, elution with a gradient of 40 to 80% ethylacetate in hexanes) to provide 0.66 g of di(tert-butyl)2-propyl-1-[4-(3,5,5-trimethyl-1,2,4-oxadiazol4(5H)-yl)butyl]-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a white solid.

Part B

The Boc protecting groups were removed from the material from Part A byacid hydrolysis as described in Example 598 Part D. The crude productwas purified by chromatography (silica gel, elution with 9:1chloroform/CMA) and dried under high vacuum at 65° C. to provide 0.0874g of2-propyl-1-[4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl]-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 144.0-146.0° C. ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d,J=7.3 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.22 (t,J=7.8 Hz, 1H), 5.44 (s, 2H), 4.22 (t, J=7.3 Hz, 2H), 3.18 (t, J=7.5 Hz,2H), 2.95 (t, J=7.9 Hz, 2H), 1.94 (q, J=7.3 Hz, 2H), 1.63-1.77 (m, 7H),1.32 (s, 6H), 0.93 (t, J=7.4 Hz, 3H); MS (APCI) m/z 395 (M+H)⁺; Anal.calcd for C₂₂H₃₀N₆O.0.3 H2O: C, 66.07; H, 7.71; N, 21.01. Found: C,65.82; H, 7.74; N, 20.90.

Example 6151-Pent4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A mixture of1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (19.45 g,61.39 mmol), prepared as described in Example 46, platinum oxide (10.00g) and trifluoroacetic acid (200 mL) was placed under hydrogen pressure(50 psi, 3.4×105 Pa) for 2 days. The reaction mixture was filteredthrough CELITE filter aid. The filtrate was concentrated under reducedpressure to provide a dark oil. The oil was chilled in an ice bath, icewas added, and the mixture was made basic (pH 14) by the addition of 1 Npotassium hydroxide. The resulting solid was isolated by filtration andthen dissolved in dichloromethane. The solution was washed sequentiallywith 1 N potassium hydroxide, water, and brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas dried under vacuum for 2 days to provide 18.0 g of1-(4-chlorobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas an oil.

Part B

Using the method of Example 57 Part A, the material from Part A wasreacted with di-tert-butyl dicarbonate (49 g, 4 eq) to provide aquantitative yield of di(tert-butyl)1-(4-chlorobutyl)-2-propyl-6,7,8,9-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a black oil.

Part C

Using the method of Example 57 Part B, the material from Part B wasreacted with potassium acetate (11.0 g, 2.0 eq) to provide 29.25 g of4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl}butylacetate as a black oil.

Part D

Using the method of Example 57 Part C, the acetate protecting group wasremoved from the material from Part C to provide 24.2 g ofdi(tert-butyl)1-(4-hydroxybutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a brown solid.

Part E

The material from Part D was oxidized using the method of Example 57Part D. The crude product was purified by chromatography (silica gel,elution with 1:1 hexanes/ethyl acetate) and dried under vacuum atambient temperature over the weekend to provide 15.5 g of di(tert-butyl)1-(4-oxobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas an amber, glassy, semi-solid.

Part F

Using the method of Example 58 Part E, the material from Part E wasreacted with freshly prepared diethyl 1-diazo-2-oxopropylphosphonate(10.22 g, 1.5 eq) to provide 15.33 g of di(tert-butyl)1-pent4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a tan solid.

Part G

Under a nitrogen atmosphere, a solution of a portion (0.75 g) of thematerial from Part F in 6 M hydrochloric acid in ethanol (10 mL) washeated at 60° C. for 1.7 hours. The reaction mixture was concentratedunder reduced pressure. The residue was made basic with 1 N potassiumhydroxide and then extracted with dichloromethane. The combined extractswere washed sequentially with water and brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by chromatography (silica gel, elution with a gradient of5-20% CMA in chloroform) to provide 0.327 g of a tan solid. Thismaterial was twice triturated with boiling diethyl ether and isolated byfiltration to provide 0.2823 g of1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 167.0-169.0° C. ¹H NMR (300 MHz, CDCl₃) δ 5.07 (s,2H), 4.25 (t, J=7.5 Hz, 2H), 3.15 (t, J=8.1 Hz, 2H), 2.18-2.84 (m, 2H),2.64-2.70 (m, 2H), 2.22-2.29 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.99 (q,J=7.4 Hz, 2H), 1.81-1.87 (m, 6H), 0.97 (t, J=7.4 Hz, 3H); MS (APCI) m/z297 (M+H)⁺; Anal. calcd for C₁₈H₂₄N₄O.0.3H₂O: C, 71.63; H, 8.22; N,18.56. Found: C, 71.60; H, 7.96; N, 18.71.

Example 6161-[3-(3-Methylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Using the method of Example 595 Part B, di(tert-butyl)1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(4.00 g, 8.05 mmol), prepared as described in Example 615, was reactedwith α-chloroacetaldoxime (1.13 g, 12.1 mmol). The crude product waspurified by chromatography (silica gel, elution with a gradient of20-40% ethyl acetate in hexanes) to provide 1.55 g of di(tert-butyl)1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a glassy solid.

Part B

Under a nitrogen atmosphere, a solution of the material from Part A in 6M hydrochloric acid in ethanol (10 mL) was heated at 60° C. for 2 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was made basic with 1 N potassium hydroxide and then extractedwith dichloromethane. The combined extracts were washed sequentiallywith water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was dried under vacuumover the weekend and then triturated with a mixture of hexanes anddiethyl ether. The resulting solid was isolated by filtration and driedto provide 0.3342 g of1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 144.0-145.0° C. ¹H NMR (300 MHz, CDCl₃) δ 5.86 (s,1H), 5.06 (bs, 2H), 4.17 (t, J=7.4 Hz, 2H), 3.05 (t, J=8.1 Hz, 2H),2.79-2.86 (m, 4H), 2.71-2.75 (m, 2H), 2.28 (s, 3H), 1.89-2.07 (m, 4H),1.80-1.84 (m, 4H), 0.95 (t, J=7.4 Hz, 3H); MS (APCI) m/z 354 (M+H)⁺;Anal. calcd for C₂₀H₂₇N₅O: C, 67.96; H, 7.70; N, 19.81. Found: C, 67.67;H, 7.83; N, 19.68.

Example 6171-[3-(3-Phenylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Under a nitrogen atmosphere, a mixture of di(tert-butyl)1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(4.00 g, 8.05 mmol), prepared as described in Example 615,α-chlorobenzaldoxime (2.51 g, 16.1 mmol), prepared as described inExample 596, anhydrous triethylamine (1.7 mL, 12.1 mmol), and anhydrousdichloromethane (25 mL) was heated at 40° C. for 18 hours. The reactionmixture was diluted with dichloromethane, washed sequentially withpotassium carbonate, water, and brine, dried over sodium sulfate, andfiltered. The filtrate was loaded onto a silica gel column (250 g) andeluted with a gradient of 30-40% ethyl acetate in hexanes. The fractionscontaining product were combined and concentrated under reduced pressureto provide 2.97 g of di(tert-butyl)1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonateas a pale yellow solid.

Part B

Under a nitrogen atmosphere, a solution of the material from Part A in 6M hydrochloric acid in ethanol (20 mL) was heated at 60° C. for 1.7hours. The reaction mixture was concentrated under reduced pressure. Theresidue was made basic with 1 N potassium hydroxide and then extractedwith dichloromethane. The combined extracts were washed sequentiallywith water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide 1.75 g of a yellow solid.This material was purified by column chromatography (silica gel, elutionwith a gradient of 10-20% CMA in chloroform) to provide 1.324 g ofproduct. This material was triturated twice with hot diethyl ether toprovide 0.85 g of a pale yellow solid. The solid was recrystallizedtwice from ethanol to provide1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 154.0-155.0° C. ¹H NMR (300 MHz, CDCl₃) δ 7.75-7.80(m, 2H), 7.42-7.49 (m, 3H), 6.34 (s, 1H), 5.01 (bs, 2H), 4.19 (t, J=7.4Hz, 2H), 3.11 (t, J=8.2 Hz, 2H), 2.94 (t, J=7.3 Hz, 2H), 2.83 (m, 2H),2.73 (m, 2H), 2.09 (p, J=8.0 Hz, 2H), 1.95 (q, J=7.4 Hz, 2H), 1.80-1.84(m, 4H), 0.95 (t,J=7.4 Hz, 3H); MS (APCI) m/z 416 (M+H)⁺.

Example 6182-Propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Under a nitrogen atmosphere, N-chlorosuccinimide (2.1 g, 16 mmol) wasadded to a solution of 3-pyridine aldoxime (2.0 g, 16 mmol) in THF (10mL). The solution was stirred at ambient temperature for 4 hours. Asolution of di(tert-butyl)1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(4.00 g, 8.05 mmol), prepared as described in Example 615, and anhydroustriethylamine (2.5 mL, 18 mmol) in THF (10 mL) was added and thereaction solution was heated at 60° C. for 18 hours. The reactionsolution was concentrated under reduced pressure to provide a black oil.The oil was dissolved in dichloromethane, washed sequentially withpotassium carbonate, water, and brine, dried over sodium sulfate, andfiltered. The filtrate was purified by column chromatography (silicagel, elution with a gradient of 20-80% ethyl acetate in hexanes) toprovide 1.0877 g of di(tert-butyl)2-propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate.

Part B

Under a nitrogen atmosphere, a solution of the material from Part A in 6M hydrochloric acid in ethanol (20 mL) was heated at 60° C. for 1.5hours. The reaction mixture was concentrated under reduced pressure. Theresidue was made basic with 1 N potassium hydroxide and then extractedwith dichloromethane. The combined extracts were washed sequentiallywith water and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, elution with a gradient of 5-20% CMA inchloroform) to provide 0.385 g of product. This material was trituratedtwice with hot diethyl ether to provide 0.2185 g of2-propyl-1-[3-(3-pyridin-3-ylisoxazol-5-yl)propyl]-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white solid, mp 168.0-170.0° C. ¹H NMR (300 MHz, CDCl₃) δ 8.98-9.01(md, 1H), 8.68-8.7 (mt, 1H), 8.11-8.15 (md, 1H), 7.38-7.43 (m, 1H), 6.38(s, 1H), 5.17 (bs, 2H), 4.20 (t, J=7.3 Hz, 2H), 3.12 (t, J=8.2 Hz, 2H),2.97 (t, J=7.3 Hz, 2H), 2.80-2.85 (m, 2H), 2.70-2.75 (m, 2H), 2.11 (p,J=8.0 Hz, 2H), 1.96 (q, J=7.4 Hz, 2H), 1.70-1.89 (m, 4H), 0.96 (t, J=7.4Hz, 3H); MS (APCI) m/z 417 (M+H)³⁰ ; Anal. calcd for C₂₄H₂₈N₆O.0.6H₂O:C, 67.46; H, 6.89; N, 19.67. Found: C, 67.19; H, 6.61; N, 19.65.

Examples 619-643

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing1-(4-chlorobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine(32 mg, 0.10 mmol, prepared as described in Example 615 Part A) andpotassium carbonate (approximately 55 mg, 0.40 mmol) inN,N-dimethylacetamide (1 mL). The test tubes were capped and heated at90° C. for approximately 16 hours. The reaction mixtures were filteredand the solvent was removed from the filtrates by vacuum centrifugation.The compounds were purified as described in Examples 71-85. The tablebelow shows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 619 None-starting material

321.1830 620 Pyrrolidine

356.2833 621 Piperidine

370.2978 622 Morpholine

372.2796 623 Hexamethyleneimine

384.3158 624 3-Hydroxypiperidine

386.2952 625 4-Hydroxypiperidine

386.2952 626 Thiomorpholine

388.2558 627 1-Methylpiperazine

385.3067 628 3-(Dimethylamino) pyrrolidine

399.3262 629 N,N′-Dimethyl-3- aminopyrrolidine

399.3273 630 N-Methylhomopiperazine

399.3264 631 3-(Hydroxymethyl)piperidine

400.3107 632 Isonipecotamide

413.3041 633 Nipecotamide

413.3047 634 1-Acetylpiperazine

413.3029 635 bis(2-Methoxyethyl)amine

418.3217 636 2-(2- Methylaminoethyl)pyridine

421.3109 637 1-(2-Methoxyethyl)piperazine

429.3309 638 4-(1-Pyrrolidinyl)-piperidine

439.3506 639 4-Phenylpiperidine

446.3255 640 1-(2-Pyridyl)piperazine

448.3183 641 1-(4-Pyridyl)-piperazine

448.3232 642 1-(2-Pyrimidyl)piperazine

449.3107 643 4-Chlorophenol

413.2120

Examples 644-700

Part A

A mixture of1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3 g,prepared as described in Example 19), platinum (IV) oxide (3 g), andtrifluoroacetic acid (50 mL) was placed under hydrogen pressure (50 psi,3.4×10⁵ Pa) on a Parr shaker for 2 days. The reaction mixture wasfiltered through a layer of CELITE filter agent and the filter cake wasrinsed with dichloromethane. The filtrate was concentrated under reducedpressure. The residue was made basic (p H 14) by the addition of 50%sodium hydroxide and then extracted with chloroform. The extract wasdried over sodium sulfate and then purified by chromatography on aHORIZON HPFC system (eluting with chloroforn/CMA in a gradient from100:0 to 70:30) to provide 1.75 g of1-(4-chlorobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a light yellow solid.

Part B

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing1-(4-chlorobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(31 mg, 0.10 mmol) and potassium carbonate (approximately 55 mg, 0.40mmol) in N,N-dimethylacetamide (1 mL). The test tubes were capped andheated at 70° C. for approximately 17 hours. The reaction mixtures werefiltered and the solvent was removed from the filtrates by vacuumcentrifugation. The compounds were purified as described in Examples71-85. The table below shows the reagent added to each test tube, thestructure of the resulting compound, and the observed accurate mass forthe isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 644 None-starting material

307.1694 645 Pyrrolidine

342.2682 646 Piperidine

356.2845 647 Morpholine

358.2638 648 Thiazolidine

360.2237 649 1-Methylpiperazine

371.2937 650 4-Hydroxypiperidine

372.2795 651 3- (Dimethylamino)pyrrolidine

385.3103 652 N,N′-Dimethyl-3- aminopyrrolidine

385.3098 653 N-Ethylpiperazine

385.3092 654 N-Methylhomopiperazine

385.3118 655 2-Piperidinemethanol

386.2896 656 3-(Hydroxymethyl)piperidine

386.2888 657 4-(Hydroxymethyl)piperidine

386.2893 658 N-Methylbenzylamine

392.2845 659 Isonipecotamide

399.2902 660 Nipecotamide

399.2894 661 (3S)-(−)-3- Acetamidopyrrolidine

399.2876 662 1-Acetylpiperazine

399.2906 663 1-Methyl-4- (Methylamino)piperidine

399.3218 664 2-Piperidineethanol

400.3098 665 4-Piperidineethanol

400.3116 666 N-(2- Hydroxyethyl)piperazine

401.3050 667 1,2,3,4- Tetrahydroisoquinoline

404.2845 668 (R)-(+)-N-Methyl-1- Phenylethylamine

406.3002 669 (S)-(−)-N-Methyl-1- Phenylethylamine

406.3007 670 4- (Ethylaminomethyl)pyridine

407.2958 671 4-(1-Pyrrolidinyl)-piperidine

425.3405 672 1-(2-Ethoxyethyl)piperazine

429.3372 673 1-Phenylpiperazine

433.3121 674 1-(2-Pyridyl)piperazine

434.3068 675 1-(4-Pyridyl)-piperazine

434.3066 676 1-(2-Pyrimdyl)piperazine

435.3006 677 4-Piperidinopiperidine

439.3589 678 4-Benzylpiperidine

446.3323 679 4-Hydroxy-4- phenylpiperidine

448.3083 680 1-(2-Furoyl)piperazine

451.2848 681 Phenol

365.2370 682 2-Cyanophenol

390.2276 683 3-Cyanophenol

390.2332 684 4-Cyanophenol

390.2289 685 3-Methoxyphenol

395.2413 686 4-Methoxyphenol

395.2477 687 Guaiacol

395.2485 688 2-Chlorophenol

399.1955 689 3-Chlorophenol

399.1946 690 4-Chlorophenol

399.1913 691 4-Hydroxybenzamide

408.2427 692 Salicylamide

408.2430 693 2-Acetamidophenol

422.2584 694 3-Acetamidophenol

422.2597 695 4-Hydroxyphenylacetamide

422.2587 696 Acetaminophen

422.2594 697 2- Dimethylaminomethylphenol

422.2943 698 2- Dimethylaminomethylphenol

422.2960 699 3,4-Dichlorophenol

433.1546 700 4- Hydroxybenzenesulfonamide

444.2099

Examples 701-775

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-4-amine (32 mg,0.10 mmol, prepared as described in Example 46) and potassium carbonate(approximately 55 mg, 0.40 mmol) in N,N-dimethylacetamide (1 mL). Thetest tubes were capped and heated at 85° C. for approximately 18 hours.The reaction mixtures were filtered and the solvent was removed from thefiltrates by vacuum centrifugation. The compounds were purified asdescribed in Examples 71-85. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 701 None-starting material

317.1542 702 2-(Methylamino)ethanol

356.2476 703 Piperidine

366.2679 704 (R)-3-Hydroxypyrrolidine

368.2467 705 Morpholine

368.2443 706 2-Ethylaminoethanol

370.2610 707 1-Methylpiperazine

381.2777 708 4-Hydroxypiperidine

382.2585 709 3-Hydroxypiperidine

382.2575 710 Thiomorpholine

384.2242 711 N-Methylfurfurylamine

392.2450 712 N-Methylcyclohexylamine

394.2995 713 N- Propylcyclopropanemethylamine

394.3004 714 N,N′-Dimethyl-3- aminopyrrolidine

395.2964 715 N-Ethylpiperazine

395.2957 716 N-Methylhomopiperazine

395.2915 717 2,6-Dimethylmorpholine

396.2796 718 3-(Hydroxymethyl)piperidine

396.2732 719 4-(Hydroxymethyl)piperidine

396.2764 720 N-Ethylaniline

402.2686 721 N-Methylbenzylamine

402.2680 722 1-Acetylpiperazine

409.2697 723 Isonipecotamide

409.2709 724 Nipecotamide

409.2695 725 1-Methyl-4- (methylamino)piperidine

409.3067 726 2-Piperidineethanol

410.2938 727 4-Piperidineethanol

410.2953 728 N-(2-Hydroxyethyl)piperazine

411.2862 729 N-Methylphenethylamine

416.2831 730 2-(2-Methylaminoethyl)pyridine

417.2759 731 4-(Ethylaminomethyl)pyridine

417.2796 732 2-Amino-1-phenylethanol

432.2751 733 1-(2-Ethoxyethyl)piperazine

439.3194 734 1-Phenylpiperazine

443.2926 735 1-(2-Pyridyl)piperazine

444.2854 736 4-Piperidinopiperidine

449.3390 737 4-Benzylpiperidine

456.3132 738 4-Hydoxy-4-phenylpiperidine

458.2898 739 1-(2-Furoyl)piperazine

461.2658 740 N-Isopropyl-1- piperazineacetamide

466.3321 741 Dibenzylamine

478.3015 742 2,2′-Dipicolylamine

480.2880 743 Phenol

375.2155 744 m-Cresol

389.2325 745 o-Cresol

389.2318 746 p-Cresol

389.2358 747 2-Fluorophenol

393.2096 748 3-Fluorophenol

393.2087 749 4-Fluorophenol

393.2070 750 2-Cyanophenol

400.2164 751 3-Cyanophenol

400.2127 752 4-Cyanophenol

400.2151 753 2,4-Dimethylphenol

403.2482 754 3,4-Dimethylphenol

403.2458 755 3-Methoxyphenol

405.2332 756 2-Methoxyphenol

405.2296 757 4-Methoxyphenol

405.2310 758 2-Chlorophenol

409.1817 759 3-Chlorophenol

409.1787 760 4-Chlorophenol

409.1805 761 4-Hydroxybenzamide

418.2222 762 Salicylamide

418.2272 763 3-Dimethylaminophenol

418.2630 764 3-tert-Butylphenol

431.2794 765 4-Hydroxyphenylacetamide

432.2422 766 4-Acetamidophenol

432.2377 767 2-Acetamidophenol

432.2415 768 3-Acetamidophenol

432.2396 769 2-Dimethylaminomethylphenol

432.2734 770 3-Hydroxybenzotrifluoride

443.2042 771 4-Hydroxybenzotrifluoride

443.2050 772 2,3-Dichlorophenol

443.1438 773 2,4-Dichlorophenol

443.1372 774 2,5-Dichlorophenol

443.1427 775 3,4-Dichlorophenol

443.1422

Examples 776-799

Part A

Platinum (IV) oxide (4 g) was added to a solution of1-(4-aminobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine(approximately 24 mmol, prepared as described in Part A of Examples349-453) in trifluoroacetic acid (80 mL), and the mixture was shakenunder hydrogen pressure (50 psi, 3.4×10⁵ Pa) for two days andsubsequently filtered through a layer of CELITE filter agent. The filtercake was washed with methanol, and the filtrate was concentrated underreduced pressure. Water (10 mL) was added, and the resulting solutionwas adjusted to pH 14 with the addition of 50% aqueous sodium hydroxide.The resulting mixture was extracted with dichloromethane, and theextracts were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to provide1-(4-aminobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part B

A reagent (0.048 mmol, 1.1 equivalents) from the table below was addedto a test tube containing1-(4-aminobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(12.5 mg, 0.044 mmol) and N,N-diisopropylethylamine (approximately 15μL, 2 equivalents) in chloroform (1 mL). The test tubes were capped andshaken for four hours. Two drops of water were added to each test tube,and the solvent was removed by vacuum centrifugation. The compounds werepurified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 776 Acetyl chloride

330.2275 777 Cyclopropanecarbonyl chloride

356.2417 778 Isobutyryl chloride

358.2600 779 Cyclopentanecarbonyl chloride

384.2771 780 Cyclohexanecarbonyl chloride

398.2882 781 Phenylacetyl chloride

406.2586 782 3-(Trifluoromethyl)benzoyl chloride

460.2296 783 1-Propanesulfonyl chloride

394.2255 784 Isopropylsulfonyl chloride

394.2260 785 1-Butanesulfonyl chloride

408.2441 786 Trifluoromethanesulfonyl chloride

420.1678 787 Benzenesulfonyl chloride

428.2078 788 2,2,2-Trifluoroethanesulfonyl chloride

434.1819 789 alpha-Toluenesulfonyl chloride

442.2266 790 Ethyl isocyanate

359.2540 791 Isopropyl isocyanate

373.2689 792 N-Propyl isocyanate

373.2713 793 N-Butyl isocyanate

387.2856 794 Cyclopentyl isocyanate

399.2846 795 Phenyl isocyanate

407.2519 796 Cyclohexyl isocyanate

413.3038 797 p-Tolyl isocyanate

421.2720 798 3-Methoxyphenyl isocyanate

437.2661 799 3-Chlorophenyl isocyanate

441.2194

Examples 800-819

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing 1-butyl-2H-pyrazolo[3,4-c]quinolin-4-aminehydrochloride (27.6 mg, 0.10 mmol, prepared as described in Part A ofExamples 579-581) and potassium carbonate (55 mg, 0.40 mmol) in DMF (1mL). The test tubes were capped and shaken overnight at ambienttemperature. The reaction mixtures were filtered and the solvent wasremoved from the filtrates by vacuum centrifugation. The compounds werepurified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 800 None-starting material —H241.1441 801 1-Bromopentane

311.2222 802 2-Iodoethanol

285.1711 803 1-Iodobutane

297.2054 804 2-Iodobutane

297.2053 805 1-(3- Bromopropyl)pyrrole

348.2174 806 2-Cyclohexylethyl bromide

351.2527 807 2-Cyanobenzyl bromide

356.1855 808 2-Bromoacetophenone

359.1871 809 1-Bromo-3- Phenylpropane

359.2220 810 3-Chlorobenzyl bromide

365.1521 811 4-Chlorobenzyl bromide

365.1548 812 2,6-Difluorobenzyl bromide

367.1742 813 2-Bromo-4′- methylacetophenone

373.1996 814 2-Bromo-4′- fluoroacetohenone

377.1789 815 4-Cyanophenacyl bromide

384.1801 816 2-Bromo-3′Methoxyacetophenone

389.2006 817 2-Bromo-4′- Methoxyacetophenone

389.1953 818 2,6-Dichlorobenzyl bromide

399.1115 819 3,4-Dichlorobenzyl bromide

399.1170

Examples 820-904

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride (34 mg, 0.098 mmol, prepared as described in Parts Athrough H of Example 51) and N,N-diisopropylethylamine (approximately 70μL, 4 equivalents) in chloroform (1 mL). The test tubes were capped andshaken for six hours. Two drops of water were added to each test tube,and the solvent was removed by vacuum centrifugation. The compounds werepurified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 820 None-starting material

270.1707 821 Acetyl chloride

312.1855 822 Propionyl chloride

326.1965 823 Cyclopropanecarbonyl chloride

338.1994 824 Butyryl chloride

340.2110 825 Methoxyacetyl chloride

342.1953 826 Pivaloyl chloride

354.2304 827 Benzoyl chloride

374.1986 828 Cyclopentylacetyl chloride

380.2487 829 Cyclohexanecarbonyl chloride

380.2419 830 m-Toluoyl chloride

388.2146 831 Phenylacetyl chloride

388.2168 832 3-Fluorobenzoyl chloride

392.1925 833 4-Fluorobenzoyl chloride

392.1896 834 4-Cyanobenzoyl chloride

399.1963 835 Hydrocinnamoyl chloride

402.2307 836 3-Methoxybenzoyl chloride

404.2108 837 p-Anisoyl chloride

404.2093 838 3-Chlorobenzoyl chloride

408.1565 839 4-Chlorobenzoyl chloride

408.1616 840 Isonicotinoyl chloride hydrochloride

375.1937 841 Nicotinoyl chloride hydrochloride

375.1913 842 Picolinoyl chloride hydrochloride

375.1948 843 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

414.2304 844 3-Dimethylaminobenzoyl chloride

417.2423 845 4-Chlorophenylacetyl chloride

422.1747 846 3-(Trifluoromethyl)benzoyl chloride

442.1840 847 3,4-Dichlorobenzoyl chloride

442.1196 848 4-(Trifluoromethoxy)benzoyl chloride

458.1784 849 Methanesulfonyl chloride

348.1522 850 Ethanesulfonyl chloride

362.1672 851 1-Propanesulfonyl chloride

376.1812 852 Isopropylsulfonyl chloride

376.1808 853 Dimethylsulfamoyl chloride

377.1767 854 1-Butanesulfonyl chloride

390.2003 855 Trifluoromethanesulfonyl chloride

402.1206 856 Benzenesulfonyl chloride

410.1689 857 1-Methylimidazole-4-sulfonyl chloride

414.1732 858 2,2,2-Trifluoromethanesulfonyl chloride

416.1376 859 2-Thiophenesulfonyl chloride

416.1233 860 alpha-Toluenesulfonyl chloride

424.1842 861 3-Fluorobenzenesulfonyl chloride

428.1556 862 4-Fluorobenzenesulfonyl chloride

428.1568 863 3-Cyanobenzenesulfonyl chloride

435.1585 864 4-Cyanobenzenesulfonyl chloride

435.1617 865 3-Methoxybenzenesulfonyl chloride

440.1798 866 4-Methoxybenzenesulfonyl chloride

440.1721 867 2-Chlorobenzenesulfonyl chloride

444.1277 868 3-Chlorobenzenesulfonyl chloride

444.1272 869 4-Chlorobenzenesulfonyl chloride

444.1278 870 3-(Trifluoromethyl)benzenesulfonyl chloride

478.1482 871 4-(Trifluoromethyl)benzenesulfonyl chloride

478.1519 872 2,4-Dichlorobenzenesulfonyl chloride

478.0887 873 2,6-Dichlorobenzenesulfonyl chloride

478.0858 874 3,4-Dichlorobenzenesulfonyl chloride

478.0838 875 3,5-Dichlorobenzenesulfonyl chloride

478.0890 876 Methyl isocyanate

327.1915 877 Ethyl isocyanate

341.2110 878 Isopropyl isocyanate

355.2263 879 Cyclopropyl isothiocyanate

369.1870 880 Pentyl isocyanate

383.2596 881 Isobutyl isothiocyanate

385.2207 882 Phenyl isocyanate

389.2116 883 Cyclohexyl isocyanate

395.2597 884 Benzyl isocyanate

403.2283 885 m-Tolyl isocyanate

403.2268 886 o-Tolyl isocyanate

403.2238 887 Phenyl isothiocyanate

405.1867 888 3-Pyridyl isothiocyanate

406.1828 889 2-Phenethyl isocyanate

417.2416 890 2-Methoxyphenyl isocyanate

419.2187 891 3-Methoxyphenyl isocyanate

419.2167 892 2-Chlorophenyl isocyanate

423.1716 893 3-Chlorophenyl isocyanate

423.1736 894 4-Chlorophenyl isocyanate

423.1716 895 3,4-Difluorophenyl isocyanate

425.1877 896 trans-2-Phenylcyclopropyl isocyanate

429.2428 897 3-Carbomethoxyphenyl isocyanate

447.2178 898 3,4-Dimethoxyphenyl isocyanate

449.2318 899 3,5-Dimethoxyiphenyl isocyanate

449.2270 900 2-(Trifluoromethoxy)phenyl isocyanate

473.1876 901 N,N-Dimethylcarbamoyl chloride

341.2104 902 2-Oxo-1-imidazolidinecarbonyl chloride

382.1967 903 4-Methyl-1-piperazinecarbonyl chloride

396.2530 904 N-Methyl-N-Phenylcarbamoyl chloride

403.2245

Examples 905-941

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinoline-4-amine (31 mg,0.10 mmol, prepared as described in Example 19) and potassium carbonate(approximately 55 mg, 0.40 mmol) in DMF (1 mL). The test tubes werecapped and heated at 50° C. for approximately 18 hours and then at 85°C. for 5 hours. The reaction mixtures were filtered and the solvent wasremoved from the filtrates by vacuum centrifugation. The compounds werepurified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 905 None-starting material

303.1352 906 2-(Methylamino)ethanol

342.2295 907 Cyclopentylamine

352.2509 908 Piperidine

352.2497 909 (R)-3-Hydroxypyrrolidine

354.2297 910 Morpholine

354.2301 911 Thiazolidine

356.1942 912 Cyclohexylamine

366.2661 913 1-Methylpiperazine

367.2617 914 4-Hydroxypiperidine

368.2452 915 Thiomorpholine

370.2053 916 Diethanolamine

372.2402 917 3-Picolylamine

375.2289 918 N-Methylfurfurylamine

378.2289 919 N-Ethylpiperazine

381.2749 920 N-Methylhomopiperazine

381.2764 921 2,6-Dimethylmorpholine

382.2625 922 N,N-Dimethyl-N′- ethylethylenediamine

383.2944 923 N-Methylbenzylamine

388.2493 924 3-Azabicyclo[3.2.2]nonane

392.2816 925 1-Acetylpiperazine

395.2555 926 Isonipecotamide

395.2561 927 1-Methyl-4- (methylamino)piperidine

395.2888 928 4-Piperidineethanol

396.2765 929 Aminoethyl)morpholine

397.2720 930 N-(2-Hydroxyethyl) piperazine

397.2731 931 bis(2- Methoxyethyl)amine

400.2716 932 1,2,3,4- Tetrahydroisoquinoline

400.2487 933 1,1- Dioxidotetrahydrothien- 3-ylamnie

402.1963 934 Methyl isonipecotate

410.2554 935 N-(3- Aminopropyl)morpholine

411.2876 936 4-(1-Pyrrolindinyl)- piperidine

421.3071 937 1-(2- Ethoxyethyl)piperazine

425.3028 938 1-Phenylpiperazine

429.2729 939 1-(2-Pyridyl)piperazine

430.2732 940 4-Benyzylpiperidine

442.2974 941 1-(2-Furoyl)piperazine

447.2495

Examples 942-1019

A reagent (0.11 nmmol, 1.1 equivalents) from the table below was addedto a test tube containing1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(27 mg, 0.10 mmol, prepared as described in Example 589) andN,N-diisopropylethylamine (approximately 34 μL, 2 equivalents) inchloroform (1 mL). The test tubes were capped and shaken for about 16hours. Water (50 μL) was added to each test tube, and the solvent wasremoved by vacuum centrifugation. The compounds were purified asdescribed in Examples 71-85. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 942 None-starting material

274.2038 943 Propionyl chloride

330.2314 944 Methyl chloroforrnate

332.2068 945 Cyclopropanecarbonyl chloride

342.2281 946 Butyryl chloride

344.2462 947 Isobutyryl chloride

344.2468 948 Methoxyacetyl chloride

346.2242 949 Methyl chlorothiolformate

348.1872 950 Cyclobutanecarbonyl chloride

356.2471 951 Isovaleryl chloride

358.2617 952 Cyclopentanecarbonyl chloride

370.2637 953 Benzoyl chloride

378.2315 954 Cyclohexanecarbonyl chloride

384.2777 955 2-Fluorobenzoyl chloride

396.2228 956 3-Fluorobenzoyl chloride

396.2219 957 4-Fluorobenzoyl chloride

396.2228 958 3-Cyanobenzoyl chloride

403.2255 959 4-Cyanobenzoyl chloride

403.2274 960 Hydrocinnamoyl chloride

406.2613 961 2-Methoxybenzoyl chloride

408.2415 962 3-Methoxybenzoyl chloride

408.2403 963 p-Anisoyl chloride

408.2409 964 2-Chlorobenzoyl chloride

412.1929 965 3-Chlorobenzoyl chloride

412.1936 966 4-Chlorobenzoyl chloride

412.1929 967 Isonicotinoyl chloride hydrochloride

379.2263 968 Nicotinoyl chloride hydrochloride

379.2217 969 Picolinoyl chloride hydrochloride

379.2234 970 Methanesulfonyl chloride

352.1825 971 Ethanesulfonyl chloride

366.1987 972 1-Propanesulfonyl chloride

380.2142 973 Isopropylsulfonyl chloride

380.2150 974 Dimethylsulfamoyl chloride

381.2038 975 1-Butanesulfonyl chloride

394.2293 976 Benzenesulfonyl chloride

414.1946 977 1-Methylimidazole-4-sulfonyl chloride

418.2022 978 2,2,2-Trifluoroethanesulfonyl chloride

420.1650 979 alpha-Toluenesulfonyl chloride

428.2090 980 o-Toluenesulfonyl chloride

428.2122 981 p-Toluenesulfonyl chloride

428.2105 982 2-Fluorobenzenesulfonyl chloride

432.1891 983 3-Fluorobenzenesulfonyl chloride

432.1877 984 4-Fluorobenzenesulfonyl chloride

432.1838 985 3-Cyanobenzenesulfonyl chloride

439.1921 986 4-Cyanobenzenesulfonyl chloride

439.1921 987 3-Methoxybenzenesulfonyl chloride

444.2036 988 4-Methoxybenzenesulfonyl chloride

444.2082 989 2-Chlorobenzenesulfonyl chloride

448.1583 990 3-Chlorobenzenesulfonyl chloride

448.1584 991 4-Chlorobenzenesulfonyl chloride

448.1583 992 Methyl isocyanate

331.2276 993 Ethyl isocyanate

345.2416 994 Isopropyl isocyanate

359.2588 995 N-Propyl isocyanate

359.2568 996 Isopropyl isothiocyanate

375.2342 997 Cyclopentyl isocyanate

385.2722 998 Cyclopropylmethyl isothiocyanate

387.2356 999 Phenyl isocyanate

393.2427 1000 Cyclohexyl isocyanate

399.2901 1001 Benzyl isocyanate

407.2578 1002 m-Tolyl isocyanate

407.2584 1003 o-Tolyl isocyanate

407.2581 1004 p-Tolyl isocyanate

407.2563 1005 Phenyl isothiocyanate

409.2182 1006 3-Pyridyl isothiocyanate

410.2164 1007 2-Methoxyphenyl isocyanate

423.2523 1008 3-Methoxyphenyl isocyanate

423.2486 1009 4-Methoxyphenyl isocyanate

423.2512 1010 2-Chlorophenyl isocyanate

427.2027 1011 3-Chlorophenyl isocyanate

427.2027 1012 4-Chlorophenyl isocyanate

427.2030 1013 trans-2-Phenylcyclopropyl isocyanate

433.2676 1014 N,N-Dimethylcarbamoyl chloride

345.2416 1015 1-Pyrrolidinecarbonyl chloride

371.2584 1016 2-Oxo-1-imidazolidinecarbonyl chloride

386.2310 1017 4-Morpholinylcarbonyl chloride

387.2515 1018 4-Methyl-1-Piperazinecarbonyl chloride

400.2810 1019 N-Methyl-N-Phenylcarbamoyl chloride

407.2577

Examples 1020-1097

A reagent (0.12 mmol, 1.2 equivalents) from the table below was added toa test tube containing1-(4-aminobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-aminetris-trifluoroacetate (64 mg, 0.10 mmol, prepared as described inExample 578) and N,N-diisopropylethylamine (approximately 90 μL, 5equivalents) in N,N-dimethylacetamide (1 mL). The test tubes were cappedand shaken for about 16 hours. Water (30 μL) was added to each testtube, and the solvent was removed by vacuum centrifugation. Thecompounds were purified as described in Examples 71-85. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 1020 None-starting material

302.2356 1021 Methyl chloroformate

360.2431 1022 Cyclopropanecarbonyl chloride

370.2581 1023 Butryrl chloride

372.2793 1024 Isobutyryl chloride

372.2797 1025 Ethyl chloroformate

374.2581 1026 Methoxyacetyl chloride

374.2524 1027 Methyl chlorothiolformate

376.2200 1028 Cyclobutanecarbonyl chloride

384.2800 1029 Isovaleryl chloride

386.2942 1030 Pentanoyl chloride

386.2930 1031 Pivaloyl chloride

386.2955 1032 tert-Butylacetyl chloride

400.3100 1033 Benzoyl chloride

406.2637 1034 Cyclohexanecarbonyl chloride

412.3082 1035 3-Cyanobenzoyl chloride

431.2566 1036 4-Cyanobenzoyl chloride

431.2582 1037 Cinnamoyl chloride

432.2789 1038 Hydrocinnamoyl chloride

434.2884 1039 2-Methoxylbenzoyl chloride

436.2724 1040 2-Chlorobenzoyl chloride

440.2225 1041 3-Chlorobenzoyl chloride

440.2231 1042 4-Chlorobenzoyl chloride

440.2261 1043 Isonicotinoyl chloride hydrochloride

407.2575 1044 Nicotinoyl chloride hydrochloride

407.2576 1045 Picolinoyl chloride hydrochloride

407.2582 1046 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

446.2876 1047 Methanesulfonyl chloride

380.2112 1048 Ethanesulfonyl chloride

394.2269 1049 1-Propanesulfonyl chloride

408.2450 1050 Isopropylsulfonyl chloride

408.2448 1051 Dimethylsulfamoyl chloride

409.2384 1052 1-Butanesulfonyl chloride

422.2617 1053 Benzenesulfonyl chloride

442.2272 1054 1-Methylimidazole-4- sulfonyl chloride

446.2353 1055 3-Methylbenzenesulfonyl chloride

456.2474 1056 alpha-Toluenesulfonyl chloride

456.2435 1057 o-Toluenesulfonyl chloride

456.2475 1058 p-Toluenesulfonyl chloride

456.2390 1059 3-Cyanobenzenesulfonyl chloride

467.2200 1060 4-Cyanobenzenesulfonyl chloride

467.2187 1061 3-Methoxybenzenesulfonyl chloride

472.2384 1062 4-Methoxybenzenesulfonyl chloride

472.2398 1063 2-Chlorobenzenesulfonyl chloride

476.1908 1064 3-Chlorobenzenesulfonyl chloride

476.1861 1065 4-Chlorobenzenesulfonyl chloride

476.1846 1066 1-Naphthalenesulfonyl chloride

492.2451 1067 2-Naphthalenesulfonyl chloride

492.2414 1068 N-Acetylsulfanilyl chloride

499.2519 1069 Methyl isocyanate

359.2596 1070 Ethyl isocyanate

373.2702 1071 Isopropyl isocyanate

387.2855 1072 N-Propyl isocyanate

387.2852 1073 N-Butyl isocyanate

401.3009 1074 sec-Butyl isocyanate

401.3026 1075 Cyclopropyl isothiocyanate

401.2458 1076 Cyclopentyl isocyanate

413.2993 1077 Cyclopropylmethyl isothiocyanate

415.2605 1078 Phenyl isocyanate

421.2702 1079 Cyclohexyl isocyanate

427.3229 1080 m-Tolyl isocyanate

435.2876 1081 Phenyl isothiocyanate

437.2459 1082 3-Pyridyl isothiocyanate

438.2480 1083 2-Tetrahydrofurfuryl isothiocyanate

445.2741 1084 Benzoyl isocyanate

449.2674 1085 2-Phenylethyl isocyanate

449.3064 1086 2-Methoxylphenyl isocyanate

451.2864 1087 3-Methoxylphenyl isocyanate

451.2798 1088 4-Methoxylphenyl isocyanate

451.2860 1089 3-Chlorophenyl isocyanate

455.2350 1090 4-Chlorophenyl isocyanate

455.2345 1091 trans-2- Phenylcyclopropyl isocyanate

461.3076 1092 3-Carbomethoxyphenyl isocyanate

479.2800 1093 N,N-Dimethylcarbamoyl chloride

373.2736 1094 1-Pyrrolidinecarbonyl chloride

399.2891 1095 1-Piperidinecarbonyl chloride

413.2986 1096 4-Morpholinecarbonyl chloride

415.2802 1097 4-Methyl-1- Piperazinecarbonyl chloride

428.3176

Examples 1098-1115

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (30 mg,0.10 mmol, prepared as described in Example 577) andN,N-diisopropylethylamine (approximately 36 μL, 2 equivalents) inchloroform (1 mL). The test tubes were capped and shaken for about 4hours. Two drops of water were added to each test tube, and the solventwas removed by vacuum centrifugation. The compounds were purified asdescribed in Examples 71-85. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Exam- Measured Mass ple Reagent R (M + H) 1098 None-starting

298.2036 1099 Propionyl chloride

354.2326 1100 Cyclobutanecarbonyl chloride

380.2464 1101 Benzoyl chloride

402.2332 1102 Cyclohexanecarbonyl chloride

408.2801 1103 Nicotinoyl chloride hydrochloride

403.2280 1104 Methanesulfonyl chloride

376.1839 1105 1-Propanesulfonyl chloride

404.2154 1106 Isopropylsulfonyl chloride

404.2087 1107 Dimethylsulfamoyl chloride

405.2098 1108 Benzenesulfonyl chloride

438.1996 1109 1-Methylimidazole-4- sulfonyl chloride

442.2025 1110 2,2,2- Trifluoroethanesulfonyl chloride

444.1700 1111 Cyclopropyl isothiocyanate

397.2207 1112 Cyclopentyl isocyanate

409.2737 1113 Phenyl isocyanate

417.2438 1114 Cyclohexyl isocyanate

423.2903 1115 3-Pyridyl isothiocyanate

434.2153

Examples 1116-1129

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(32 mg, 0.10 mmol, prepared as described in Example 64) andN,N-diisopropylethylamine (approximately 27 μL, 1.5 equivalents) inN,N-dimethylacetamide (1 mL). Test tubes were capped and shaken forabout 4 hours. Two drops of water were added to each test tube, and thesolvent was removed by vacuum centrifugation. The compounds werepurified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Exam- Measured Mass ple Reagent R (M + H) 1116 None-starting material

298.2029 1117 Acetyl chloride

340.2144 1118 Benzoyl chloride

402.2336 1119 Hydrocinnamoyl chloride

430.2639 1120 Nicotinoyl chloride hydrochloride

403.2256 1121 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

442.2607 1122 Methanesulfonyl chloride

376.1814 1123 Dimethylsulfamoyl chloride

405.2071 1124 Benzenesulfonyl chloride

438.1994 1125 alpha-Toluenesulfonyl chloride

452.2145 1126 Isopropyl isocyanate

383.2566 1127 Cyclopropyl isothiocyanate

397.2189 1128 Phenyl isocyanate

417.2445 1129 N-Methyl-N- Phenylcarbamoyl chloride

431.2592

Examples 1130-1176

Part A

A mixture of1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminehydrochloride (2.8 g, prepared as described in Examples 454-488),platinum (IV) oxide (2.1 g), and triflouroacetic acid (43 mL) was placedunder hydrogen pressure (50 psi, 3.4×10⁵ Pa) on Parr shaker for 2 days.The reaction mixture was filtered through a layer of CELITE filter agentand the filter cake was rinsed with methanol. The filtrate wasconcentrated under reduced pressure. The residue was diluted with water(10 mL), made basic (pH 14) by the addition of 50% sodium hydroxide andthen extracted with dichloromethane. The extract was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by chromatography on a HORIZON HPFC system (40+cartridgeeluting with chloroform/CMA in a gradient from 100:0 to 80:20) toprovide 2.0 g of1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a light yellow solid.

Part B

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(29 mg, 0.10 mmol) and potassium carbonate (approximately 55 mg, 0.40mmol) in N,N-dimethylacetamide (1 mL). The test tubes were capped andheated at 70° C. (amines) or 85° C. (phenols) for approximately 17hours. The reaction mixtures were filtered and the solvent was removedfrom the filtrates by vacuum centrifugation. The compounds were purifiedas described in Examples 71-85. The table below shows the reagent addedto each test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 1130 None-starting material

293.1557 1131 Pyrrolidine

328.2524 1132 Piperidine

342.2643 1133 Morpholine

344.2464 1134 2-Ethylaminoethanol

346.2614 1135 3-Hydroxypiperidine

358.2613 1136 4-Hydroxypiperidine

358.2633 1137 3-(Dimethylamino)pyrrolidine

371.2914 1138 N-Methylhomopiperazine

371.2959 1139 2-Piperidinemethanol

372.2749 1140 3-(Hydroxymethyl)piperidine

372.2794 1141 4-(Hydroxymethyl)piperidine

372.2793 1142 N-Methylbenzylamine

378.2680 1143 Isonipecotamide

385.2697 1144 (3s)-(-)-3- Acetamidopyrrolidine

385.2710 1145 1-Acetylpiperazine

385.2723 1146 2-Piperidineethanol

386.2931 1147 4-Piperidineethanol

386.2928 1148 N-(2-Hydroxyethyl)piperazine

387.2910 1149 4-(Ethylaminomethyl)pyridine

393.2790 1150 1-(2-Methoxyethyl)piperazine

401.3011 1151 4-(1-Pyrrolidinyl)-piperidine

411.3260 1152 1-(2-Ethoxyethyl)piperazine

415.3208 1153 1-Phenylpiperazine

419.2944 1154 1-(2-Pyridyl)piperazine

420.2886 1155 4-Piperidinopiperidine

425.3397 1156 1-Hydroxyethylethoxypiperazine

431.3148 1157 1-(2-Furoyl)piperazine

437.2685 1158 2-Piperidin-1-ylmethyl- piperidine

439.3556 1159 1-Cinnamylpiperazine

459.3239 1160 1-Phenyl-1,3,8- triazospiro[4.5]decan-4-one

488.3132 1161 Phenol

351.2188 1162 2-Cyanophenol

376.2125 1163 3-Cyanophenol

376.2157 1164 4-Cyanophenol

376.2140 1165 3-Methoxyphenol

381.2270 1166 4-Methoxyphenol

381.2278 1167 Guaiacol

381.2270 1168 2-Chlorophenol

385.1785 1169 4-Chlorophenol

385.1780 1170 4-Hydroxybenzamide

394.2255 1171 3-Dimethylaminophenol

394.2589 1172 2,4-Dichlorophenol

419.1378 1173 2,5-Dichlorophenol

419.1363 1174 3,4-Dichlorophenol

419.1374 1175 3,5-Dichlorophenol

419.1381 1176 4-Hydroxybenzenesulfonamide

430.1886

Examples 1177-1191

Part A

DMF (50 mL) was added to a mixture of1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (3 g, 12.5 mmol,prepared as described in Example 9), 4-bromobutylphthalimide (3.9 g,13.7 mmol), and potassium carbonate (5.2 g, 37.5 mmol).

The reaction mixture was heated at 60° C. with stirring under a nitrogenatmosphere for about 18 hours. The reaction mixture was filtered toremove excess potassium carbonate. The filtrate was diluted with waterand then extracted with ethyl acetate. The extract was dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by chromatography on a HORIZON HPFC system(silica gel, eluting first with ethyl acetate and then with a gradientof methanol in ethyl acetate) to provide 2.0 g of2-{4-[4-amino-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-2-yl]butyl}-1H-isoindole-1,3 (2H)-dione.

Part B

The material from Part A was combined with hydrazine monohydrate (1.1mL. 5 eq) and ethanol (100 mL). The reaction mixture was heated atreflux for 2 hours and then allowed to cool to ambient temperatureovernight. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure to provide 0.8 g of2-(4-aminobutyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part C

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing2-(4-aminobutyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(31 mg, 0.10 mmol) and N,N-diisopropylethylamine (approximately 35 μL, 2equivalents) in N,N-dimethylacetamide (1 mL). The test tubes were cappedand shaken for about 16 hours. Two drops of water were added to eachtest tube, and the solvent was removed by vacuum centrifugation. Thecompounds were purified as described in Examples 71-85. The table belowshows the reagent added to each test tube, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Example Reagent R Measured Mass (M + H) 1177 None-starting material

312.2203 1178 Acetyl chloride

354.2316 1179 Benzoyl chloride

416.2444 1180 Hydrocinnamoyl chloride

444.2769 1181 Nicotinoyl chloride hydrochloride

417.2406 1182 Isopropylsulfonyl chloride

418.2296 1183 Dimethylsulfamoyl chloride

419.2213 1184 Trifluoromethanesulfonyl chloride

444.1689 1185 Benzenesulfonyl chloride

452.2150 1186 alpha-Toluenesulfonyl chloride

466.2242 1187 Ethyl isocyanate

383.2586 1188 Cyclopropyl isothiocyanate

411.2358 1189 Cyclopropylmethyl isothiocyanate

425.2496 1190 Phenyl isocyanate

431.2590 1191 Benzyl isocyanate

445.2752

Examples 1192-1197

A reagent (0.12 mmol, 1.2 equivalents) from the table below and asolution of potassium tert-butoxide (150 μL of 1 M in THF, 1.5 eq) wereadded to a test tube containing1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinoline-4-amine (30 mg,0.10 mmol) in DMF (1 mL). The tubes were capped and stirred (magneticstir bar) at ambient temperature for about 65 hours. Aqueoushydrochloric acid (300 μL of 1 N) and peracetic acid (57 μL of 32 wt %)were added to each tube; then stirring was continued for an additional 3hours. The solvent was removed by vacuum centrifugation. The compoundswere purified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 1192 None-starting

303.1352 1193 Ethanethiol

361.1699 1194 2-Propanethiol

375.1861 1195 Methyl thioglycolate

405.1585 1196 Thiophenol

409.1690 1197 Furfuryl mercaptan

413.1659

Example 1198

Under a nitrogen atmosphere, potassium tert-butoxide (218 μL of 1 M inTHF, 1.5 eq) was added to a solution of1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinoline-4-amine (44 mg,0.145 mmol) and butanethiol (19 μL, 0.174 mmol) in DMF (1.5 mL). Thereaction mixture was stirred at ambient temperature overnight. Peraceticacid (76 μL of 32 wt %) was added and the reaction mixture was stirredfor 2 hours. The reaction mixture was acidified (pH 3) by the additionof 1 N hydrochloric acid and then loaded onto a solid phase extractioncartridge (Waters, MCX 6 cc). The reaction mixture was pushed throughthe cartridge with light nitrogen pressure to provide fraction 1. Thecartridge was eluted sequentially with methanol (5 mL) andammonia/methanol (5 mL of 1 N) to provide fractions 2 and 3respectively. The solvent was removed by vacuum centrifugation toprovide1-[4-(butylsulfonyl)butyl]-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine,measured mass (M+H): 389.1989.

Example 1199 4-Amino-1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-7-ol

Dichloromethane (1 mL) was added to a vial containing1,2-diethyl-7-methoxy-2H-pyrazolo[3,4-c]quinolin-4-amine (20 mg, 0.074mmol, prepared as described in Example 573). The reaction mixture wasstirred at 0° C. for 5 minutes. Cold boron tribromide (370 μL of 1 M indichloromethane, 0.37 mmol) was added dropwise and the reaction mixturewas stirred at 0° C. for 20 minutes. The ice bath was removed and thereaction mixture was stirred for about 3 hours. The solvent wasevaporated. The residue was combined with methanol (2 mL) and 6 Nhydrochloric acid (500 μL); and then stirred for 1 hour. The mixture wasmade basic by the addition of 6 M sodium hydroxide and a portion of thesolvent was evaporated. The residue was partitioned betweendichloromethane (25 mL) and water (25 mL). The layers were separated.The aqueous layer was evaporated to provide a yellow solid. The solidwas suspended in methanol. The methanol was evaporated and the residuewas purified as described in Examples 71-85 to provide thetrifluoroacetate salt of4-amino-1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-7-ol, measured mass(M+H): 257.1408.

Example 12007-(Benzyloxy)-1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Chloroform (2 mL) and cesium carbonate (32.6 mg, 0.1 mmol) were added toa vial containing 4-amino-1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-7-ol(17 mg, 0.05 mmol) and the mixture was stirred at ambient temperaturefor 5 minutes. Benzyl bromide (6.54 μL, 0.055 mmol) was added and thereaction mixture was stirred at 50° C. for 30 minutes. Analysis by LCMSindicated that only a small amount of product had formed. The chloroformwas evaporated and the residue was dissolved in N,N-dimethylacetamide.The reaction mixture was stirred at 50° C. for about 1 hour. The solventwas evaporated and the residue was purified as described in Examples71-85 to provide the trifluoroacetate salt of7-(benzyloxy)-1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-4-amine, measuredmass (M+H): 423.2190.

Examples 1201 & 1202

N,N-Dimethylacetamide (2 mL) and cesium carbonate (32.6 mg, 0.1 mmol)were added to vials containing4-amino-1,2-diethyl-2H-pyrazolo[3,4-c]quinolin-7-ol (17 mg, 0.05 mmol)and the mixture was stirred at ambient temperature for 5 minutes. Areagent (6.54 μL, 0.055 mmol) from the table below was added to a vialand the reaction mixture was stirred at 50° C. for 4 hours. The solventwas evaporated and the residue was purified as described in Examples71-85. The table below shows the reagents used, the structure of theresulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M +H) 1201 alpha-Bromo-p- xylene

437.2349 1202 4-Chlorobenzyl bromide

457.1809

Examples 1203-1206

A boronic acid (2.1 eq, 0.11 mmol) from the table below and n-propylalcohol (720 μL) were added to a vial containing4-amino-2-ethyl-1-(2-phenylethyl)-2H-pyrazolo[3,4-c]quinolin-7-yltrifluoromethanesulfonate (23 mg, 0.05 mmol, prepared as described inExample 576). The vial was purged with nitrogen. Palladium (II) acetate(1.12 mg, 10 mole %), 2 M aqueous sodium carbonate (250 μL), water (50μL), and triphenylphosphine (2.6 mg (20 mole %) in 100 μL of n-propylalcohol) were sequentially added. The reaction mixture was heated at 80°C. with stirring for 1 hour, allowed to cool to ambient temperature, andthen filtered through a plug of glass wool. The plug was washed withn-propyl alcohol, methanol, and dichloromethane. The filtrate wasevaporated and the residue was purified as described in Examples 71-85.The table below shows the reagents used, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 1203 Phenylboronic acid

393.2108 1204 4-Methylphenylboronic acid

407.2201 1205 Pyridine-3-boronic acid

394.2031 1206 Furan-3-boronic acid

383.1852

Examples 1207-1216

Part A

1-(2-Methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (2.4 g, 9.99 mmol,prepared as described in Example 9), potassium carbonate (5.5 g, 39.9mmol), 3-chloroiodopropane (1.2 mL, 11.0 mmol), and DMF (110 mL) werecombined and heated at 40° C. overnight. The reaction mixture wasdiluted with water and then extracted with ethyl acetate. The combinedextracts were washed with water and concentrated under reduced pressure.The residue was purified twice by chromatography on a HORIZON HPFCsystem (silica gel eluting with ethyl acetate) to provide2-(3-chloropropyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part B

A reagent (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing2-(3-chloropropyl)-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(32 mg, 0.10 mmol) and potassium carbonate (approximately 55 mg, 0.40mmol) in N,N-dimethylacetamide (1 mL). The test tubes were capped andheated at 70° C. (amines) or 85° C. (phenols) for approximately 18hours. The reaction mixtures were filtered and the solvent was removedfrom the filtrates by vacuum centrifugation. The compounds were purifiedas described in Examples 71-85. The table below shows the reagent addedto each test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 1207 Morpholine

368.2472 1208 2-(Propylamino)ethanol

384.2784 1209 N,N′-Dimethyl-3- aminopyrrolidine

395.2943 1210 3-(Hydroxymethyl)piperidine

396.2797 1211 N-Methylbenzylamine

402.2664 1212 1-Acetylpiperazine

409.2721 1213 Nipecotamide

409.2733 1214 Phenol

375.2200 1215 3-Methoxyphenol

405.2329 1216 3-Chlorophenol

409.1805

Examples 1217-1241

Part A

A mixture of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (11.37 g,47.78 mmol, prepared as described in Example 15), n-propanol (80 mL),and 1 M hydrochloric acid (60 mL) was heated in an oil bath at 80° C.for 1 hour and then allowed to cool to ambient temperature. Solid sodiumcarbonate was added with stirring to neutralize the hydrochloric acidand to serve as a base in the next step.

Part B

tert-Butyl 2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)ethylcarbamate(11.36 g, 312.84 mmol, prepared as described in Example 51), n-propanol(20 mL), and palladium (II) acetate (143 mg, 0.64 mmol) were added tothe mixture from Part A. The reaction mixture was degassed andbackfilled with nitrogen three times and then heated at 100° C. for twodays. The reaction mixture was allowed to cool to ambient temperatureand the n-propanol was removed under reduced pressure. The residue wasdiluted with chloroform (250 mL), washed with water (2×100 mL), driedover magnesium sulfate, filtered, and than concentrated under reducedpressure to provide a light yellow solid. This material was purified bychromatography on a HORIZON HPFC system (silica gel eluting with agradient of 0-45% of 80:20 CMA:chloroform in chloroform) to provide 2.47g of a light yellow solid. This material was suspended in acetonitrile(25 mL), sonicated for about 15 seconds, isolated by filtration, rinsedwith acetonitrile, and dried to provide 2.25 g of tert-butyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-1-yl)ethylcarbamateas a white solid.

Part C

Hydrochloric acid (3 mL of 2.7 M in ethanol) was added to a suspensionof tert-butyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-1-yl)ethylcarbamate(0.52 g) in ethanol (10 mL). The mixture was heated at 80° C. for about1 hour and then concentrated under reduced pressure. The residue waspartitioned between water (50 mL) and dichloromethane (30 mL). Thelayers were separated. The aqueous layer was made basic with ammoniumhydroxide and then extracted with dichloromethane (2×50 mL). Thecombined organics were washed with brine (1×50 mL), dried over magnesiumsulfate, filtered, and then concentrated under reduced pressure toprovide 0.29 g of crude product as a white solid. The reaction wasrepeated using 2.05 g of starting material to provide 1.18 g of crudeproduct as a white solid. The two lots were combined and purified bychromatography on a HORIZON HPFC system (silica gel eluting with agradient of 20-60% of 80:20 CMA:chloroform in chloroform) to provide0.48 g of1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amine asa white solid.

Part D

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]-1,8-naphthyridin-4-amine(26 mg, 0.10 mmol) and N,N-diisopropylethylamine (approximately 36 μL, 2equivalents) in chloroform (2 mL). The test tubes were capped and shakenfor about 4 hours. Two drops of water were added to each test tube, andthe solvent was removed by vacuum centrifugation. The compounds werepurified as described in Examples 71-85. The table below shows thereagent added to each test tube, the structure of the resultingcompound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 1217 None-starting material only

271.1696 1218 Acetyl chloride

313.1781 1219 Propionyl chloride

327.1962 1220 Cyclopropanecarbonyl chloride

339.1948 1221 Butyryl chloride

341.2108 1222 Isobutyryl chloride

341.2107 1223 Benzoyl chloride

375.1966 1224 Cyclohexanecarbonyl chloride

381.2433 1225 Nicotinoyl chloride hydrochloride

376.1888 1226 Methanesulfonyl chloride

349.1472 1227 Ethanesulfonyl chloride

363.1638 1228 1-Propanesulfonyl chloride

377.1736 1229 Isopropylsulfonyl chloride

377.1794 1230 1-Butanesulfonyl chloride

391.1938 1231 1-Benzenesulfonyl chloride

411.1636 1232 2,2,2- Trifluoroethanesulfonyl chloride

417.1358 1233 Methyl isocyanate

328.1909 1234 Ethyl isocyanate

342.2059 1235 Isopropyl isocyanate

356.2222 1236 N-Propyl isocyanate

356.2213 1237 Cyclopentyl isocyanate

382.2394 1238 Cyclohexyl isocyanate

396.2547 1239 1-Pyrrolidinecarbonyl chloride

368.2217 1240 1-Piperidinecarbonyl chloride

382.2379 1241 4-Morpholinecarobonyl chloride

384.2181

Example 1242N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclopropylamide

Cyclopropanecarbonyl chloride (454 μL, 5.00 mmol) was added to a stirredsolution of1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 64, 595 mg, 2.00 mmol) andtriethylamine (895 μL, 6.4 mmol) in dichloromethane (18 mL). Thesolution was stirred for 15 minutes at room temperature and then wasconcentrated under reduced pressure to yield a yellow solid that wasdissolved in methanol (20 mL). Concentrated hydrochloric acid (4 mL) wasadded to the resulting solution, and the reaction was heated at refluxfor 20 hours and allowed to cool to room temperature. Aqueous sodiumcarbonate (15 mL of 2 M) was added, and the methanol was removed underreduced pressure. The resulting mixture was extracted four times withchloroform. The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product(1.2 g) was purified by IFC using a silica cartridge followed followedby recrystallization from 35% ethyl acetate in hexanes (50 mL). Thecrystals were dried overnight on the filter funnel and then driedovernight under vacuum at 98° C. to provide 463 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclopropylamideas a white solid, mp 192-193° C.

MS (APCI) m/z 366 (M+H)⁺;

Anal. Calcd for C₂₁H₂₇N₅O: C, 69.01; H, 7.45; N, 19.16. Found: C, 68.66;H, 7.46; N, 19.13.

Example 1243N-{2-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}cyclopropylamide

The methods described in Example 1242 were used treat1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(0.500 g, 1.60 mmol), prepared as described in Example 590, withcyclopropanecarbonyl chloride and to isolate and purify the finalproduct to provide 267 mg ofN-{2-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}cyclopropylamideas a white solid, mp 180-181° C.

MS (APCI) m/z 382 (M+H)⁺;

Anal. Calcd for C₂₁H₂₇N₅O₂: C, 66.12; H, 7.13; N, 18.36. Found: C,66.06; H, 7.48; N, 18.35.

Example 12441-(2-Amino-2-methylpropyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

The methods described in Parts A through C of Example 64 were followedusing ethylhydrazine oxalate in lieu of propylhydrazine oxalate in PartA to provide tert-butyl2-[3-(aminocarbonyl)-1-ethyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate,which was recrystallized from 75:25 ethyl acetate:hexanes to yield awhite solid, mp 178-180° C. Anal. Calcd for C₁₅H₂₆N₄O₃: C, 58.04; H,8.44; N, 18.05. Found: C, 58.08; H, 8.72; N, 18.14.

The methods described in Parts D through G of Example 64 were then usedto convert tert-butyl2-[3-(aminocarbonyl)-1-ethyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamateto1-(2-amino-2-methylpropyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine.The final crude product (5.08 g) was recrystallized from a mixture of35% ethyl acetate in hexanes (100 mL) and ethyl acetate (200 mL). Themother liquor was concentrated under reduced pressure, and the residuewas purified by IFC (silica cartridge) to provide1-(2-amino-2-methylpropyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine asa beige solid, mp 234-235° C.

MS (APCI) m/z 284 (M+H)⁺;

Anal. Calcd for C₁₆H₂₁N₅: C, 67.82; H, 7.47; N, 24.71. Found: C, 67.60;H, 7.38; N, 24.57.

Examples 1245-1251

The method described in Example 65 can be used to treat1-(2-amino-2-methylpropyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-aminewith the acid chlorides shown in the following table to provide thecompounds shown in the following table.

Example Reagent Name R 1245 Acetyl chloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1- dimethylethyl]acetamide

1246 Nicotinoyl chloride hydrochloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-l,1- dimethylethyl]nicotinamide

1247 Isonicotinoyl chloride hydrochloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1- dimethylethyl]isonicotinamide

1248 4-Fluorobenzoyl chloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1- dimethylethyl]-4-fluorobenzamide

1249 3,4-Difluorobenzoyl chloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1- dimethylethyl]-3,4- difluorobenzamide

1250 Propionyl chloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1- dimethylethyl]propionamide

1251 Cyclopropanecarbonyl chloride N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin--yl)-1,1- dimethylethyl]cyclopropylamide

Example 1252N-[2-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide

Under a nitrogen atmosphere, a solution of1-(2-amino-2-methylpropyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine(609 mg, 2.15 mmol) in dichloromethane (60 mL) was cooled to 0° C.Triethylamine (326 mg, 3.22 mmol) and methanesulfonyl chloride (246 mg,2.15 mmol) were sequentially added. The reaction was stirred at 0° C.for five hours and then allowed to warm to room temperature slowly andstirred overnight. Water was added, and the aqueous layer was separatedand extracted four times with chloroform. The combined organic fractionswere dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by IFC (silicacartridge) followed by recrystallization from acetonitrile. The crystalswere dried overnight on the vacuum filter funnel to provide 363 mg ofN-[2-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamideas a white solid, mp 229-230° C.

MS (APCI) m/z 362 (M+H)⁺;

Anal. Calcd for C₁₇H₂₃N₅O₂S: C, 56.49; H, 6.41; N, 19.37. Found: C,56.46; H, 6.77; N 19.70.

Example 12531-(4-Chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Ethyl 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxylate (163 g) wasprepared using a modification of the procedure described in Part A ofExample 19. Methylhydrazine was used instead of ethylhydrazine oxalate.After all the reagents were added, the reaction mixture was stirredovernight instead of two hours. Dichloromethane was used for extractionduring the work-up procedure, and the combined extracts were not dried.The product was obtained as a dark oil, which was treated according tothe method of Part B of Example 46 to provide5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxylic acid.

Part B

To a solution of the carboxylic acid from Part A (0.666 mol) indichloromethane (1 L) and DMF (0.5 mL) at 0° C. was added oxalylchloride (64.0 mL, 0.73 mol). The reaction was stirred for one hour atambient temperature. An analysis by HPLC indicated the presence ofstarting material, and additional oxalyl chloride (35 mL) was added. Thereaction was stirred at ambient temperature for one hour andconcentrated under reduced pressure. The residue was dissolved in asmall volume of dichloromethane and added slowly to concentratedammonium hydroxide (888 mL of 15 M) cooled to approximately 0° C. Thereaction was stirred at ambient temperature for two days. A precipitatewas present and was isolated by filtration and washed with water. Thefiltrate was extracted with dichloromethane. The organic fraction wasdried over sodium sulfate, filtered, and concentrated under reducedpressure to yield a tan solid that was combined with the isolatedprecipitate to provide 103 g of5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxamide.

Part C

A solution of 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carboxamide (39g, 0.181 mol) and triethylamine (75 mL, 0.54 mol) in dichloromethane(600 mL) was cooled to approximately 0° C., and trifluoroaceticanhydride (31 mL, 0.22 mol) was added. The reaction was stirred for onehour, and then saturated aqueous ammonium chloride (50 mL) was added.The mixture was diluted with water and extracted with dichloromethane.The combined organic fractions were dried over sodium sulfate andconcentrated under reduced pressure to5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile as a dark brownoil.

Part D

Potassium acetate (35.5 g, 0.362 mol) and bromine (12 mL, 0.235 mol)were added to a solution of the material from Part C in acetic acid (362mL), and the reaction was stirred for two hours at ambient temperature.An analysis by LC/MS indicated the presence of starting material, andadditional bromine (0.5 equivalent) was added. The reaction was stirredfor two more hours and again was found to be incomplete. Additionalbromine (0.5 equivalent) was added, and the reaction was stirred for onehour. Aqueous sodium bisulfite (1 mL) was added, and the mixture wasstirred until it became colorless. The acetic acid was removed underreduced pressure, and water was added to the residue. The resultingmixture was extracted with dichloromethane. The combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified through a plug of silica gel(eluting with 70:30 hexanes:ethyl acetate) to provide 51 g of4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile as a darkoil.

Part E

The method described in Part F of Example 46 was used to couple4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile (16.0 g,60.0 mmol) and 2-aminophenylboronic acid hydrochloride (20.8 g, 0.120mol). After the mixture was heated at 115° C. for 24 hours, it wascooled to ambient temperature and filtered through a plug of silica gel(eluting with 3:2 chloroform/methanol). The filtrate was concentratedunder reduced pressure and dissolved in ethanol (300 mL). Hydrogenchloride (45 mL of a 4 M solution in ethanol) was added to the solution,and the reaction was heated at reflux for two hours and then cooled toambient temperature. A precipitate formed and was isolated by filtrationand washed with ethanol to provide1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminehydrochloride. The filtrate was concentrated under reduced pressure andthe resulting solid was dissolved in dichloromethane and water. The pHof the solution was raised to 14 using 50% aqueous NaOH while keepingthe temperature at 0° C. by adding ice. The layers were separated, theaqueous layer was extracted with additional dichloromethane, the organiclayers were combined, dried over Na2SO4, filtered and concentrated to adark yellow oily solid. The residue was purified by chromatography usinga HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA inchloroform) followed by recrystallization from acetonitrile to provide1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine. Thissolid was purified as light tan crystals, mp 188-189° C.

MS (APCI) m/z 289 (M+H)⁺;

Anal. calcd for C₁₅H₁₇ClN₄: C, 62.39; H, 5.93; N, 19.40. Found: C,62.60; H, 5.99; N, 19.67.

Example 1254N-[4-(4-Amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamide

Methanesulfonamide (1.5 g, 16.5 mmol) was added to a suspension ofsodium hydride (60% dispersion in mineral oil, 0.660 g, 16.5 mmol) inDMF (10 mL); the reaction was stirred for five minutes.1-(4-Chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.952 g,3.3 mmol) in DMF (1 mL) and sodium iodide (123 mg, 0.825 mmol) weresequentially added. The reaction was heated at 80° C. for four hours,allowed to cool to ambient temperature, and poured into ice water (70mL). The resulting mixture was extracted with dichloromethane (6×50 mL),and the combined extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified twice bychromatography using a HORIZON HPFC system (40+M cartridge, eluting with0-30% CMA in chloroform first and 5-10% methanol in dichloromethanesecond) followed by recrystallizafion from acetonitrile to provide 440mg ofN-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamideas light tan crystals, mp 188-189° C.

MS (APCI) m/z 289 (M+H)⁺;

Anal. calcd for C₁₅H₁₇CIN₄: C, 62.39; H, 5.93; N, 19.40. Found: C,62.60; H, 5.99; N, 19.67.

Example 12551-(4-Chlorobutyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Ethyl 5-(4-chlorobutyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate(175 g) was prepared using a modification of the procedure described inPart A of Example 19. Hydroxyethylhydrazine was used instead ofethylhydrazine oxalate. After all the reagents were added, the reactionmixture was stirred overnight instead of two hours.

Part B

A solution of ethyl5-(4-chlorobutyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate (165 g,0.600 mol) and iodomethane (187 mL, 3.00 mol) in THF (1.2 L) was cooledto 0° C. Sodium hydride (28.8 g of a 60% dispersion in mineral oil,0.720 mol) was added slowly while maintaining the temperature below 10°C. The reaction was allowed to warm to ambient temperature and stirredovernight. Aqueous ammonium chloride and water were added, and themixture was extracted with dichloromethane. The combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure to provide ethyl5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate as a darkbrown oil.

Part C

A solution of the material from Part B in ethanol (500 mL) was combinedwith 6 M aqueous sodium hydroxide (200 mL, 1.20 mol), and the reactionwas stirred at ambient temperature for 5 hours. The ethanol was removedunder reduced pressure, and the residue was stirred with water for fiveminutes. The solution was adjusted with 3 N aqueous hydrochloric acid topH 4; a precipitate formed. The mixture was stirred for 30 minutes, andthe precipitate was then isolated by filtration, washed with water,dried on the filter funnel for two hours to provide5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid,which was dissolved in dichloromethane. The resulting solution was driedover sodium sulfate, filtered, and then used in Part D.

Part D

A modification of the method described in Part B of Example 1253 wasfollowed. After the second additional of oxalyl chloride, the reactionwas stirred for 18 hours at ambient temperature. After the reaction withammonium hydroxide was stirred for three hours, the precipitate was notisolated by filtration, but the mixture was extracted several times withdichloromethane. The combined extracts were dried, filtered, andconcentrated to provide5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide as a darkoil, which was treated with trifluoroacetic anhydride according to themethod of Part C of Examples 1253 to provide5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile as adark brown oil.

Part E

Potassium acetate (193 g, 1.97 mol) and bromine (69 mL, 1.4 mol) wereadded to a solution of the carbonitrile from Part D in acetic acid (1L), and the reaction was stirred for 24 hours at ambient temperature. Ananalysis by LC/MS indicated the presence of starting material, andadditional bromine (15 mL) was added. The reaction again was found to beincomplete. Additional bromine (15 mL) was added, and the reaction wasthen treated according to the work-up procedure described in Part D ofExample 1253 to provide 144 g of4-bromo-5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrileas a brown oil, which was used without purification.

Part F

2-Aminophenylboronic acid hydrochloride (16.2 g, 93.5 mmol), potassiumcarbonate (42.5 g, 308 mmol), DME (333 mL), water (166 mL), and4-bromo-5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile(30 g, 93.5 mmol) were combined in a flask, which was then evacuatedthree times and filled with nitrogen.Dichlorobis(triphenylphosphine)palladium(II) (0.65 g, 0.94 mmol) wasthen added, and the reaction was heated at 110° C. for one hour. Ananalysis by HPLC indicated the presence of starting material, andadditional 2-aminophenylboronic acid hydrochloride (16.2 g, 93.5 mmol)and dichlorobis(triphenylphosphine)palladium(II) (0.65 g, 0.94 mmol)were added. The reaction was then heated at reflux overnight and allowedto cool to ambient temperature. Water (30 mL) was added, and the mixturewas extracted with ethyl acetate. The combined extracts were dried oversodium sulfate, filtered through a layer of CELITE filter agent, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (eluting sequentially with 25% ethylacetate in hexanes and 75% ethyl acetate in hexanes) to provide 18 g of4-(2-aminophenyl)-5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrileas a maroon oil.

Part G

Acetyl chloride (15 mL, 216 mmol) was added to ethanol (170 mL) at 0° C.A solution of the material from Part F in ethanol (100 mL) was added,and the resulting solution was heated at reflux for two hours andallowed to cool to ambient temperature overnight. The ethanol wasremoved under reduced pressure. The residue was diluted withdichloromethane (100 mL) and adjusted to pH 12 with the addition of iceand 50% w/w aqueous sodium hydroxide. The aqueous fraction was extractedwith dichloromethane (3×100 mL), and the combined organic fractionsdried over sodium sulfate, filtered, and concentrated under reducedpressure to provide a semi-solid. The semi-solid was triturated withdiethyl ether and isolated by filtration to provide 10 g of1-(4-chlorobutyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine.A small portion of the product was recrystallized from acetonitrile toprovide white crystals, mp 156-157° C.

MS (APCI) m/z 333 (M+H)⁺;

Anal. calcd for C₁₇H₂₁CIN₄O: C, 61.35; H, 6.36; N, 16.83. Found: C,61.51; H, 6.65; N, 17.01.

Example 1256N-{4-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]butyl}methanesulfonamide

The method described in Example 1254 was used to treat1-(4-chlorobutyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine(1.1 g, 3.3 mmol) with methanesulfonamide pretreated with sodium hydridein the presence of sodium iodide. The crude was purified bychromatography using a HORIZON HPFC system (40+M cartridge, eluting with0-30% CMA in chloroform) followed by recrystallization from acetonitrileto provide 600 mg ofN-{4-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]butyl}methanesulfonamideas white crystals, mp 159-161° C.

MS (APCI) m/z 392 (M+H)⁺;

Anal. calcd for C₁₈H₂₅N₅O₃S: C, 55.22; H, 6.44; N, 17.89. Found: C,55.40; H, 6.33; N, 18.13.

Example 1257N-[3-(4-Amino-2H-pyrazolo[3,4-c]quinolin-1-yl)propyl]methanesulfonamidehydrochloride

A mixture ofN-[3-(4-amino-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)propyl]methanesulfonamide(Example 584, 0.410 g, 1.37 mmol), hydrogen bromide (0.7 mL of a 48%solution in water, 13.7 mmol) and acetonitrile (7 mL) was stirredovernight at ambient temperature. The solvent was removed under reducedpressure, and the residue was dissolved in water and treated with 50%w/w aqueous sodium hydroxide. The resulting solution was washed withdichloromethane and then adjusted to pH 4 with the addition ofconcentrated hydrochloric acid. A precipitate formed, was isolated byfiltration, and was dried on the filter funnel to provide 0.39 g ofN-[3-(4-amino-2H-pyrazolo[3,4-c]quinolin-1-yl)propyl]methanesulfonamidehydrochloride as a white powder, mp >250° C.

MS (APCI) m/z 320 (M+H)⁺;

Anal. calcd for C₁₄H₁₇N₅O₂S.H₂O.HCl: C, 44.98; H, 5.39; N, 18.73. Found:C, 44.88; H, 5.27; N, 18.57.

Example 12581-(4-Amino-2-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

Part A

A mixture sodium tert-butoxide (23.0 g, 0.240 mol) and ethanol (200 mL)was stirred for 30 minutes at 0° C.; most of the solid was dissolved. Amixture of diethyl oxalate (32.6 mL, 0.240 mol) and4-hydroxy4-methyl-2-pentanone (25.0 mL, 0.200 mol) was added slowly, andthe reaction was stirred for ten minutes at 0° C. before the addition ofacetic acid (100 mL). The reaction was warmed to ambient temperature andstirred for ten minutes. Potassium acetate (29.4 g, 0.300 mol) andbutylhydrazine oxalate (30.0 g, 0.200 mol) were sequentially added. Thereaction was stirred overnight at ambient temperature, and the aceticacid was removed under reduced pressure. The residue was adjusted to pH14 with the addition of 50% w/w aqueous sodium hydroxide whilemaintaining the temperature at 0° C. with the addition of ice. Themixture was extracted with dichloromethane; the combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by chromatography on a HORIZONHPFC system (65+M cartridge, eluting with 0 to70% ethyl acetate inhexanes) to provide 26 g of ethyl1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate as ayellow oil.

Part B

Ethyl 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate (26g, 97 mmol) and ammonia (160 mL of a 7 N solution in methanol) wereheated at 150° C. in a stainless steel reactor for 42 hours and allowedto cool to ambient temperature. The volatiles were removed under reducedpressure to provide1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxamide as ablack oil, which was treated with trifluoroacetic anhydride (40 mL, 289mmol) and triethylamine (53 mL, 386 mmol) according to a modification ofthe method of Part C of Example 1253 to provide2-(1-butyl-3-cyano-1H-pyrazol-5-yl)-1,1-dimethylethyl trifluoroacetateas a dark brown oil. The reaction with trifluoroacetic anhydride wasstirred for three hours.

Part C

Potassium carbonate (20 g, 145 mmol) was added to a solution of thetrifluoroacetate from Part B in ethanol (192 mL) and water (57 mL), andthe mixture was stirred at ambient temperature for two hours and thenfiltered to remove a solid. The filtrate was concentrated under reducedpressure, and the residue was partitioned between dichloromethane andwater. The aqueous fraction was extracted with dichloromethane, and thecombined organic fractions were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bychromatography on a HORIZON HPLC system (60I cartridge, eluting with 0to 50% ethyl acetate in hexanes to provide 18 g of1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile as ayellow oil.

Part D

The method described in Part F of Examples 1 through 4 was used to treat1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (18 g,81 mmol) with potassium acetate (16.7 g, 171 mmol) and bromine (4.6 mL,89 mmol). After the acetic acid was removed under reduced pressure, theresidue was diluted with dichloromethane (100 mL) and adjusted to pH 12with the addition of 50% w/w aqueous sodium hydroxide and ice whilemaintaining the temperature at 0° C. The resulting mixture was extractedwith dichloromethane, and the combined extracts were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct was purified by chromatography on a HORIZON HPFC system (60icartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 13g of1-butyl4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrileas a yellow oil.

Part E

A modification of the method described in Part H of Example 1255 wasused to treat1-butyl-4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile(2.7 g, 9.2 mmol). Two equivalents of 2-aminophenylboronic acidhydrochloride (3.2 g, 18.4 mmol) and 2 mol %dichlorobis(triphenylphosphine)palladium(II) (0.126 g, 0.18 mmol) wereadded at the beginning of the reaction, and the reaction was heated atreflux for five hours. The crude product was purified by chromatographyon a HORIZON HPFC system (40+M cartridge, eluting with 0 to 50% ethylacetate in hexanes to provide4-(2-aminophenyl)-1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile.

Part F

The method described in Part G of Example 1255 was used to treat thematerial from Part E with the modification that the reaction was heatedat reflux for three hours. The crude product was purified bychromatography and recrystallization according to the methods describedin Example 1256 to provide 210 mg of1-(4-amino-2-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas white crystals, mp 171-172° C.

MS (APCI) m/z 313 (M+H)⁺;

Anal. calcd for C₁₈H₂₄N₄O: C, 69.20; H, 7.74; N, 17.93. Found: C, 69.00;H, 8.07; N, 18.13.

The mother liquor from the recrystallization was concentrated to providean additional 0.78 g of product.

Example 12591-(4-Amino-2-butyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

The methods described in Example 586 were used to hydrogenate1-(4-amino-2-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol(0.78 g, 2.5 mmol) in the presence of platinum (IV) oxide (0.78 g) andtrifluoroacetic acid (20 mL) and purify the product to provide 0.21 g of1-(4-amino-2-butyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas off-white crystals, mp 130° C.

MS (APCI) m/z 317 (M+H)⁺;

Anal. calcd for C₁₈H₂₈N₄O.0.12 H₂O: C, 67.86; H, 8.93; N, 17.58. Found:C, 67.54; H, 9.15; N, 17.57.

Example 12601-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol

Part A

The method described in Part A of Example 1258 was followed usinghydroxyethylhydrazine (13.5 mL, 0.200 mol) instead of butylhydrazineoxalate. The crude product was purified by chromatography on a HORIZONHPFC system (65+M cartridge, eluting with 0 to 70% ethyl acetate inhexanes followed by ethyl acetate) to provide 24 g of ethyl1-(2-hydroxyethyl)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylateas a dark yellow oil.

Part B

A solution of ethyl1-(2-hydroxyethyl)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate(24.6 g, 95.9 mmol) in THF (191 mL) was cooled to 0° C. Sodium hydride(4.6 g of a 60% dispersion in mineral oil, 110 mmol) was added, andiodomethane (6.6 mL, 105 mmol) was added dropwise over a period of tenminutes. The reaction was allowed to warm to ambient temperature andstirred for six hours. The work-up procedure described in Part B ofExample 1255 was followed to provide ethyl5-(2-hydroxy-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylateas a light brown oil.

Part C

The methods described in Part B of Example 1258 were used to treat thematerial from Part B with ammonia (160 mL of a 7 N solution in methanol)followed by trifluoroacetic anhydride (60 mL, 287 mmol) to provide2-[3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethyltrifluoroacetate.

Part D

The method described in Part C of Example 1258 was used to treat thetrifluoroacetate from Part C with the modification that the reaction wasstirred overnight. The product,5-(2-hydroxy-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile,was treated according to the method described in Part D of Example 1258with the modification that the crude product was not purified.4-Bromo-5-(2-hydroxy-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile(10 g) was obtained as a yellow oil.

Part E

The methods described in Parts E and F of Example 1258 were followedusing4-bromo-5-(2-hydroxy-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile(7.0 g, 23 mmol) as the starting material to provide 2.0 g of1-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-olas tan crystals, mp 171-172° C.

MS (APCI) m/z 315 (M+H)⁺;

Anal. calcd for C₁₇H₂₂N₄O₂: C, 64.95; H, 7.05; N, 17.82. Found: C,64.79; H, 6.99; N, 17.89.

The mother liquor from the recrystallization of the final product wasconcentrated to provide additional material.

Example 12611-[4-Amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol

The methods described in Example 586 were used to hydrogenate1-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol(1.75 g, 5.5 mmol) in the presence of platinum (IV) oxide (1.5 g) andtrifluoroacetic acid (20 mL) and purify the product with themodification that before recrystallization, the product was alsotriturated with acetonitrile.1-[4-Amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol(1.0 g) was obtained as white crystals, mp 163-165° C.

MS (APCI) m/z 319 (M+H)⁺;

Anal. calcd for C₁₇H₂₆N₄O₂: C, 64.13; H, 8.23; N, 17.6. Found: C, 64.01;H, 8.37; N, 17.74.

Example 12621-[4-Amino-2-(2-hydroxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol

Under a nitrogen atmosphere, boron tribromide (6 mL of a 1 M solution indichloromethane) was added to a solution of1-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol(0.500 g, 1.59 mmol) in dichloromethane (8 mL), and the reaction wasstirred for four hours. The dichloromethane was removed under reducedpressure, and the residue was dissolved in a mixture of ethanol and 3 Nhydrochloric acid. A solution of 7 N ammonia in methanol was added, andthen the solvent was removed under reduced pressure. The treatment withammonia and the concentration were repeated two more times. The crudeproduct was purified by chromatography using a HORIZON HPFC system (40+Mcartridge, eluting with 0-30% CMA in chloroform) followed by triturationwith acetonitrile and recrystallization from acetonitrile to provide 115mg of1-[4-amino-2-(2-hydroxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-olas white crystals, mp 196-198° C.

MS (APCI) m/z 301 (M+H)⁺;

Anal. calcd for C₁₆H₂₀N₄O: C, 63.98; H, 6.71; N, 18.65. Found: C, 64.05;H, 6.97; N, 18.82.

Example 12631-(7-Amino-2-ethyl-5-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)-2-methylpropan-2-ol

Part A

The method described in Part A of Example 1258 was followed usingethylhydrazine oxalate (100 g, 666 mmol) instead of butylhydrazineoxalate. The crude product was purified by chromatography on silica gel(1.6 kg, eluting sequentially with 30% ethyl acetate in hexanes andethyl acetate) to provide 75 g of ethyl1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate.

Part B

The methods described in Part B of Example 1258 were used to treat thematerial from Part A with ammonia (500 mL of a 7 N solution in methanol)followed by trifluoroacetic anhydride (132 mL, 936 mmol) andtriethylamine (174 mL, 1.25 mol) to provide2-(3-cyano-1-ethyl-1H-pyrazol-5-yl)-1,1-dimethylethyl trifluoroacetate.

Part C

The method described in Part C of Example 1258 was used to treat thetrifluoroacetate from Part B with potassium carbonate (65 g, 470 mmol).The crude product was purified by chromatography on silica gel (600 g,eluting sequentially with 30% ethyl acetate in hexanes and 50% ethylacetate in hexanes) to provide 44 g of1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile as adark yellow oil.

Part D

A solution of iodine monochloride in dichloromethane (10.8 mL of 2 M,21.6 mmol) was added to a mixture of1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (2.0 g,10.3 mmol), dichloromethane (17 mL) and freshly ground potassiumcarbonate (2.9 g, 22 mmol). The reaction was stirred for 18 hours. Thework-up and purification procedures described in Part D of Example 588were followed to provide 1.8 g of1-ethyl-5-(2-hydroxy-2-methylpropyl)-4-iodo-1H-pyrazole-3-carbonitrileas a white solid.

Part E

Under a nitrogen atmosphere,1-ethyl-5-(2-hydroxy-2-methylpropyl)4-iodo-1H-pyrazole-3-carbonitrile(900 mg, 2.81 mmol), propargyltrimethylsilane (0.8 mL, 5.6 mmol),copper(I) iodide (107 mg, 0.562 mmol),dichlorobis(triphenylphosphine)palladium(II) (197 mg, 0.281 mmol),triethylamine (1.2 mL, 8.4 mmol) and acetonitrile (14 mL) were combinedand then heated at reflux for five hours. The reaction mixture wascooled to ambient temperature, diluted with ethyl acetate, and thenfiltered through a layer of silica gel. The filtrate was concentratedunder reduced pressure. The residue was purified by chromatography on aHORIZON HPFC system (40+M cartridge, eluting with a gradient of 0 to 80%ethyl acetate in hexanes) to provide1-ethyl-5-(2-hydroxy-2-methylpropyl)4-(3-trimethylsilylprop-1-ynyl)-1H-pyrazole-3-carbonitrileas a yellow oil.

Part F

The method described in Part F of Example 588 was used to treat thematerial from Part E with ammonia (30 mL of a 7 N solution in methanol)with the modification that the reaction was heated for 48 hours.Following chromatographic purification according to the method describedin Part F of Example 588, the product was recrystallized fromacetonitrile to provide 40 mg of1-(7-amino-2-ethyl-5-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)-2-methylpropan-2-olas yellow crystals, mp 134-135° C.

MS (APCI) m/z 249 (M+H)⁺;

Anal. calcd for C₁₃H₂₀N₄O: C, 62.88; H, 8.12; N, 22.56. Found: C, 62.86;H, 8.03; N, 22.62.

Examples 1264-1273

Part A

1-(2-Aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-aminedihydrochloride, prepared according to the method described in Parts Athrough H of Example 51 was stirred with aqueous sodium hydroxide at pH13. The mixture was adjusted to pH 8 with the addition of hydrochloricacid, and the resulting mixture was extracted with dichloromethane. Theextracts were concentrated under reduced pressure to provide1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine.

Part B

Under a nitrogen atmosphere, a solution of1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.0equivalent) and triethylamine (3.0 equivalents) in chloroform (startingmaterial is at a concentration of 0.008 M) was cooled to 0° C., and asolution of a reagent from the table below (1.0 equivalent) inchloroform was added. The reaction was stirred for between two and fourhours and then concentrated under reduced pressure. In some examples,the residue was mixed with water and extracted twice with chloroform ordichloromethane. The combined extracts were then concentrated underreduced pressure. For each example, the residue was purified bychromatography once or twice using an INTELLIFLASH system (eluting witha gradient of either CMA in chloroform or methanol in chloroform). Thepure product was dried in a vacuum oven overnight at 75° C. to 90° C. toprovide the product shown in the table below. Additional purificationmethods, and analytical data for each compound are given below thetable.

Examples 1264-1273

Example Reagent R 1264 Cyclopropanecarbonyl chloride

1265 Isopropyl isocyanate

1266 3,4-Difluorophenyl isocyanate

1267 Nicotinoyl chloride hydrochloride

1268 Acetyl chloride

1269 Propionyl chloride

1270 Methanesulfonyl chloride

1271 Ethyl isocyanate

1272 4-Fluorophenyl isocyanate

1273 Ethyl chloroformate

Example 1264

The reaction was carried out with the starting material at aconcentration of 0.3 M. N,N-Diisopropylethylamine (4 equivalents) wasused instead of triethylamine. The chromatography fractions wereconcentrated to a small volume, and hexanes were added to form aprecipitate. The precipitate was collected by filtration and dried asdescribed above to provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]cyclopropanecarboxamidewas obtained as a white powder, mp 215-217° C.

MS (APCD) m/z 338 (M+H)⁺;

Anal. calcd for C₁₉H₂₃N₅O₁: C, 67.63; H, 6.87; N, 20.76. Found: C,67.30; H, 6.73; N, 20.51.

Example 1265

N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-isopropylureawas obtained as a white powder, mp 197.0-198.0° C.

MS (APCI) m/z 355 (M+H)⁺;

Anal. calcd for C₁₉H₂₆N₆O₁: C, 64.38; H, 7.39; N, 23.71. Found: C,64.06; H, 7.65; N, 23.73.

Example 1266

The chromatography fractions were concentrated to a small volume, andhexanes were added to form a precipitate. The precipitate was collectedby filtration and dried as described above in Part B to provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-(3,4-difluorophenyl)ureaas a white powder, mp 211-212° C.

MS (APCI) m/z 425 (M+H)⁺;

Anal. calcd for C₂₂H₂₂F₂N₆O₁: C, 62.25; H, 5.22; N, 19.8. Found: C,61.90; H, 5.08, N, 19.57.

Example 1267

N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]nicofinamidewas obtained as a white powder, mp 219.0-221.0° C.

MS (APCI) m/z 375 (M+H)⁺;

Anal. calcd for C₂₁H₂₂N₆O₁: C, 67.36; H, 5.92; N, 22.44. Found: C,67.08; H, 5.84; N, 22.32.

Example 1268

N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]acetamidewas obtained as a white powder, mp 185.0-186.0° C.

MS (APCI) m/z 312 (M+H)⁺;

Anal. calcd for C₁₇H₂₁N₅O₁: C, 65.57; H, 6.80; N, 22.49. Found: C,65.42; H, 6.70; N, 22.69.

Example 1269

After the product was dried, it was dissolved in 2 M sodium carbonate,and the resulting solution was extracted twice with chloroform. Thecombined extracts were concentrated to a small volume, and hexanes wereadded to form a precipitate. The precipitate was collected by filtrationand dried as described above in Part B to provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]propanamideas an off-white solid, mp 184.0-185.0° C.

MS (APCI) m/z 326 (M+H)⁺;

Anal. calcd for C₁₈H₂₃N₅O₁: C, 64.44; H, 7.24; N, 20.88. Found: C,64.13; H, 6.91; N, 20.94.

Example 1270

The addition purification methods described for Example 1269 werefollowed to provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]methanesulfonamideas a white powder, mp 187.0-188.0° C.

MS (APCI) m/z 355 (M+H)⁺;

Anal. calcd for C₁₆H₂₁N₅O₂S₁: C, 55.31; H, 6.09; N, 20.16. Found: C,55.05; H, 6.22; N, 20.13.

Example 1271

After the product was purified twice by chromatography as described inPart B above, it was recystallized from acetonitrile. The crystals weredried in a vacuum oven for two days at 90° C. to provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-ethylureaas a white powder, mp 206.0-207.0° C.

MS (APCI) m/z 341 (M+H)⁺;

Anal. calcd for C₁₈H₂₄N₆O₁: C, 63.51; H, 7.11; N, 24.69. Found: C,63.58; H, 6.89; N, 24.78.

Example 1272

The addition purification methods described for Example 1269 werefollowed. Before the precipitate was dried, it was purified bychromatography using a HORIZON HPFC system (eluting with 0% to 15%methanol in chloroform). It was then dried as described in Part B aboveto provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-(4-fluorophenyl)ureaas a white solid, mp 201.0-202.0° C.

MS (APCI) m/z 407 (M+H)⁺;

Anal. calcd for C₂₂H₂₃F₁N₆O₁: C, 65.01; H, 5.70; N, 20.68. Found: C,64.64; H, 5.72; N, 20.63.

Example 1273

It was determined that much of the product remained in the aqueous layerduring the work-up procedure. The aqueous layer was adjusted to pH 9with the addition of 2 M aqueous sodium carbonate and then extractedthree times with dichloromethane. The combined extracts wereconcentrated to a small volume, and hexanes were added to form aprecipitate. The precipitate was collected by filtration and dried asdescribed above in Part B to provide ethyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate as alight yellow solid, mp 143-144° C.

MS (APCI) m/z 342 (M+H)⁺;

Anal. calcd for C₁₈H₂₃N₅O₂: C, 63.32; H, 6.79; N, 20.51. Found: C,62.98; H, 6.84; N, 20.37.

Example 1274N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-4-fluorobenzamide

Under a nitrogen atmosphere, a solution of1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.250 g,0.928 mmol), triethylamine (0.30 g, 3.0 mmol), and 4-fluorobenzoylchloride (0.18 g, 1.1 mmol) in dichloromethane (7 mL) was stirred fortwo hours and then concentrated under reduced pressure. The residue wasdissolved in methanol, and 1 N hydrochloric acid was added. The reactionwas stirred for three days at room temperature and then heated at refluxovernight. A precipitate was present and was isolated by filtration andstirred with 2 M aqueous sodium carbonate. The resulting mixture wasextracted with dichloromethane. The combined extracts were thenconcentrated under reduced pressure. The residue was purified bychromatography using an INTELLIFLASH system (eluting with 0% to 30% CMAin chloroform). The pure product was dried in a vacuum oven overnight at90° C. to provideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-4-fluorobenzamideas a white powder, mp 198-199° C.

MS (APCI) m/z 392 (M+H)⁺;

Anal. calcd for C₂₂H₂₂FN₅O: C, 67.50; H, 5.66; N, 17.89. Found: C,67.20; H, 6.01; N, 18.10.

Example 12751-[2-(1,1-Dioxidoisothiazolidin-2-yl)ethyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Under a nitrogen atmosphere, a solution of1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.228 g,0.848 mmol) and N,N-diisopropylethylamine (0.604 mL, 3.39 mmol) inchloroform (6.67 mL) was cooled to 0° C. A solution of3-chloropropanesulfonyl chloride (0.113 mL, 0.933 mmol) in chloroform(10 mL) was added. An analysis by HPLC indicated that the reaction wasnot progressing. N-Methylpyrrolidone (12 mL) was added, and the reactionwent to completion. The solvents were removed under reduced pressure toprovideN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-3-chloropropane-1-sulfonamide.

Part B

Under a nitrogen atmosphere, a solution of the material from Part A and1,8-diazabicyclo[5,4,0]undec-7-ene (0.161 g, 1.1 mmol) in DMF (2.5 mL).The reaction was stirred overnight at room temperature. The solvent wasremoved under reduced pressure, and the residue was purified bychromatography twice using an INTELLIFLASH system (eluting with 0% to40% CMA in chloroform). The chromatography fractions were concentratedto a small volume, and hexanes were added to form a precipitate. Theprecipitate was collected by filtration and dried in a vacuum ovenovernight at 90° C. to provide1-[2-(1,1-dioxidoisothiazolidin-2-yl)ethyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 201-202° C.

MS (APCI) m/z 374 (M+H)⁺;

Anal. calcd for C₁₈H₂₃N₅O₂S: C, 57.89; H, 6.21; N, 18.75. Found: C,57.78; H, 6.51; N, 18.56.

Example 1276 (4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methanol

Part A

Pyridine (40 mL, 492 mmol) was added in a single portion to a chilledsolution (0° C.) solution of indole (48 g, 410 mmol) in diethyl ether(820 mL). Ethyl chlorooxoacetate (50 mL, 451 mmol) was added dropwise.The resulting suspension was allowed to warm to ambient temperature overa period of 20 hours. The solid was isolated by filtration and washedwith diethyl ether. The solid was combined with water (1 L), stirred for1 hour, and then isolated by filtration to provide 75 g of ethyl(1H-indol-3-yl)(oxo)acetate.

Part B

Acetyl chloride (19 mL, 273 mmol), acetic acid (30 mL), andethylhydrazine oxalate (41 g, 272 mmol) were added sequentially to asuspension of methyl 1H-indol-3-yl(oxo)acetate (37 g, 180 mmol) inethanol (910 mL). The reaction mixture was heated at reflux for 18hours, cooled to ambient temperature, and concentrated under reducedpressure to a small volume. Dichloromethane (100 mL) and ice were added,and the mixture was adjusted to pH 14 with the addition of 50% w/wsodium hydroxide. A precipitate formed. The dichloromethane was removedunder reduced pressure, and the precipitate was isolated by filtration,triturated with hot acetonitrile, and isolated by filtration to provide26 g of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tansolid.

Part C

Under a nitrogen atmosphere, a mixture of2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (10 g, 46.8 mmol),N,N,N,N-tetramethylethylenediamine (31 mL), and THF (520 mL) was chilledto 0° C. A solution of n-butyllithium in hexanes (56 mL of 2.5 M) wasadded dropwise. After the addition was complete the reaction mixture wasstirred for 5 minutes and then DMF (72 mL) was added dropwise. Thereaction mixture was warmed to ambient temperature and stirred for 1hour. 1 N hydrochloric acid was added and the reaction mixture wasstirred for 1 hour. The reaction mixture was concentrated under reducedpressure to about half the original volume and then diluted with waterand extracted with dichloromethane. The combined extracts were driedover sodium sulfate, filtered, and then concentrated under reducedpressure to provide a dark yellow oil. The oil was combined withacetonitrile and stirred for 20 minutes. A bright yellow solid wasisolated by filtration to provide 4 g of2-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde asa yellow powder. An additional 3 g of material was isolated from themother liquor.

Part D

2-Ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde(1.0 g, 4.1 mmol) was combined with phosphorus oxychloride (4 mL) andheated at 90° C. for 10 minutes. Analysis by LCMS showed the desiredproduct with a small amount of a trichloro species in which chloride hadreplaced the 4-hydroxy group and the aldehyde to provide a geminaldichloride group. The reaction mixture was cooled to ambienttemperature, poured into a mixture of ammonium hydroxide (50 mL) andice, and then stirred for 20 minutes. A solid was isolated by filtrationand air dried to provide a tan solid.

Part E

Sodium borohydride (310 mg) was added in portions over a period of 20minutes to a suspension of material from Part D in methanol (20 mL). Thereaction was stirred for 30 minutes; a precipitate was present. Theprecipitate was isolated by filtration and dried on the vacuum filterfunnel to provide(4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methanol.

Part F

The material from Part E was combined with ammonia (50 mL of a 7 Nsolution in methanol), and the reaction was heated in a pressure vesselfor 18 hours at 150° C., allowed to cool to room temperature, andfurther cooled to 0° C. A precipitate was present and was isolated byfiltration, washed with a small volume of methanol, and recrystallizedfrom a mixture of acetonitrile and methanol to provide 0.19 g of(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methanol as goldcrystals, mp 255-256° C.

MS (APCI) m/z 243 (M+H)⁺;

Anal. calcd for C₁₃H₁₄N₄O: C, 64.45; H, 15.82; N, 23.12. Found: C,64.31; H, 1 5.66; N, 23.14.

Examples 1277-1281

Part A

Acetyl chloride (2 equivalents), acetic acid (methyl1H-indol-3-yl(oxo)acetate is at a concentration of 6 M), and thehydrazine or hydrazine salt indicated in the table below (1.5equivalents) were added sequentially to a 0.2 M suspension of methyl1H-indol-3-yl(oxo)acetate in ethanol. The reaction mixture was heated atreflux for 18 hours. The reaction mixture was cooled to ambienttemperature, and further cooled to 0° C. if necessary to form aprecipitate. For Examples 1278 and 1281, acetonitrile was added aftermost of the reaction solvent was removed under reduced pressure to causethe precipitate to form. The product was purified according to themethod shown in the table below.

Part B

A 0.3 M solution of the material from Part A in phosphorus oxychloridewas heated at 90° C. for 30 minutes. The reaction mixture was cooled toroom temperature, poured into a mixture of ammonium hydroxide (50 mL)and ice, and then stirred for 20 minutes to one hour. A solid wasisolated by filtration and air-dried. For Example 1278, the reaction washeated at reflux for three hours, and the ammonium hydroxide mixture wasextracted with dichloromethane. The combined extracts were dried oversodium sulfate, filtered, concentrated under reduced pressure, purifiedby chromatography on a HORIZON HPFC system (40+M column, eluting with 0%to 30% CMA in chloroform), and dried under high vacuum.

Part C

The material from Part B was combined with ammonia (7 N solution inmethanol), and the reaction was heated in a pressure vessel for 18 to 24hours at 150° C. and allowed to cool to room temperature. The tablebelow shows the structure of the product. The isolation and purificationof the product are given below the table.

Examples 1277-1281

Example Hydrazine Purification Method in Part A R 1277 MethylhydrazineTrituration with acetonitrile —CH₃ 1278 Ethylhydrazine oxalateChromatography (silica gel, —CH₂CH₃ eluting with 0% to 30% CMA inchloroform) 1279 Propylhydrazine oxalate Recrystallized from —CH₂CH₂CH₃acetonitrile 1280 Butylhydrazine oxalate Recrystallized from—CH₂CH₂CH₂CH₃ acetonitrile 1281 Methoxyethyl hydrazine None —CH₂CH₂OCH₃dihydrochloride

Example 1277

Upon cooling to room temperature, a precipitate formed. The precipitatewas isolated by filtration and recrystallized from 9:1acetonitrile:methanol to provide2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine as tan crystals, mp 218-219°C.

MS (APCI) m/z 199 (M+H)⁺;

Anal. calcd for C₁₁H₁₀N₄: C, 66.65; H, 5.08; N, 28.26. Found: C, 66.70;H, 5.13; N, 28.22.

Example 1278

The solvent was removed under reduced pressure, and the residue waspartitioned dichloromethane and water. The aqueous layer was extractedwith dichloromethane, and the combined organic fractions were dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide a white solid. The solid was purified by chromatography on aHORIZON HPFC system (40+M column, eluting with 0% to 30% CMA inchloroform) followed by recrystallization from acetonitrile to provide2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white crystals, mp240-241° C.

MS (APCI) m/z 213 (M+H)⁺;

Anal. calcd for C₁₂H₁₂N₄: C, 67.91; H, 5.70; N, 26.40. Found: C, 67.69;H, 5.80; N, 26.60.

Example 1279

Crystals formed upon cooling to room temperature, and the crystals weredissolved in hot methanol and purified by chromatography using anINTELLIFLASH system (silica gel, eluting with 0% to 30% CMA inchloroform) followed by recrystallization from a mixture of acetonitrileand methanol to provide 2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine ascolorless needles, mp 225-227° C.

MS (APCI) m/z 227 (M+H)⁺;

Anal. calcd for C₁₃H₁₄N₄: C, 69.00; H, 6.24; N, 24.76. Found: C, 69.24;H, 6.27; N, 25.04.

Example 1280

Crystals formed upon cooling to room temperature, and the crystals weredissolved in hot methanol and purified by chromatography using anINTELLIFLASH system (silica gel, eluting with 0% to 30% CMA inchloroform) followed by recrystallization from acetonitrile to provide2-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as pink crystals, mp 194-195°C.

MS (APCI) m/z 241 (M+H)⁺;

Anal. calcd for C₁₄H₁₆N₄: C, 69.97; H, 6.71; N, 23.31. Found: C, 69.92;H, 6.74; N, 23.49.

Example 1281

Upon cooling to 0° C., a precipitate formed. A portion of theprecipitate was recrystallized from acetonitrile to provide2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine as tan crystals,mp 230-231° C.

MS (APCI) m/z 243 (M+H)⁺;

Anal. calcd for C₁₃H₁₄N₄O: C, 64.45; H, 5.82; N, 23.12. Found: C, 64.43;H, 5.93; N, 23.02.

Example 1282 2-(4-Amino-2H-pyrazolo[3,4-c]quinolin-2-yl)ethanol

2-(2-Methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine was treated withboron tribromide to give2-(4-amino-2H-pyrazolo[3,4-c]quinolin-2-yl)ethanol.

Anal. calcd for C₁₂H₁₂N₄O: C, 63.15; H, 5.30; N, 24.55. Found: C, 63.06;H, 5.27; N, 24.69.

Example 1283 1-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)-2-methylpropan-2

4-Bromo-1-ethyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile(Parts A-F of Example 62) (1.36 g, 5.00 mmol),4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronic acid (Part A ofExample 56) (2.38 g, 10.0 mmol), potassium carbonate (1.04 g, 7.50mmol), DME (16 mL), water (8 mL), anddichlorobis(triphenylphosphine)palladium(II) (0.0175 g, 0.025 mmol) werecombined in a flask, which was then evacuated three times and filledwith nitrogen. The reaction was heated at 95° C. for two days. Water wasadded, and the aqueous layer was separated and extracted four times withchloroform. The combined organic fractions were dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct was purified by IFC (silica cartridge) to provide 211 mg of ayellow solid. The solid was heated at reflux in 1 M hydrogen chloride inethanol for 19 hours. Aqueous sodium carbonate (35 mL of 2 M) was added,and the ethanol was removed under reduced pressure. The mixture wasextracted four times with chloroform, and the combined extracts weretreated as described above. The crude product was purified bychromatography on a HORIZON HPFC system (silica cartridge) followed byrecrystallization from acetonitrile to provide 130 mg of1-(4-amino-2-ethyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)-2-methylpropan-2-olas a white solid, mp 277-279° C. MS (APCI) m/z 286 (M+H)⁺;

Anal. Calcd for C₁₅H₁₉N₅O: C, 63.14; H, 6.71; N, 24.54. Found: C, 62.98;H, 7.02; N, 24.77.

Example 1284 N-[2-(4-Amino-2-propyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)ethyl]4-fluorobenzamide

Part A

A modification of the method described in Example 610 was used to coupletert-butyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate (2.08g, 5.82 mmol) (Example 51, Parts A through G) with3-[(tert-butoxycarbonyl)amino]pyridin-4-ylboronic acid (2.77 g, 11.6mmol). After the first purification by IFC, 0.44 g of tert-butyl2-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)ethylcarbamate was obtained as a yellow solid.

Part B

The material from Part A was mixed with methanol (20 mL) andconcentrated hydrochloric acid (2 mL) and heated at reflux for 30minutes and allowed to cool to room temperature. Dichloromethane (25mL), triethylamine (3 mL), and 4-fluorobenzoyl chloride (0.476 g, 3.0mmol) were sequentially added. The reaction was carried out as describedin Example 1242. Following purification by IFC, the product was purifiedby chromatography again using HORIZON HPFC system (40+M cartridge,eluting with methanol in chloroform) followed by recrystallization from1:1 ethanol:propyl acetate. The crystals were isolated by filtration,washed with ethanol:propyl acetate, and dried overnight on the vacuumfilter funnel to provide 114 mg ofN-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)ethyl]4-fluorobenzamideas a white solid, mp 317-318° C.

MS (APCl) m/z 393 (M+H)⁺;

Anal. Calcd for C₂₁H₂₁FN₆O: C, 64.27; H, 5.39; N, 21.41. Found: C,64.11; H, 5.45; N, 21.67.

Example 12853-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile

Part A

4,4-Dimethyl-5-nitropentan-2-one was made according to the literatureprocedure; see Kloetzel, M. C. J. Am. Chem. Soc., 69, pp.2271-2275(1947). Under a nitrogen atmosphere, a solution of nitropentanone (9.55g, 60.0 mmol) was cooled to 0° C. Diethyl azodicarboxylate (11.5 g, 66mmol) and tributylphosphine (26.71 g, 132 mmol) were sequentially added.The reaction was stirred for one hour at 0° C. and then for one hour atroom temperature. The solvent was removed under reduced pressure, andthe residue was purified by chromatography on a HORIZON HPFC system (65Icartridge, eluting with dichloromethane). The resulting oil was treatedwith hexane; a precipitate formed and was removed by fitration. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by chromatography on a HORIZON HPFC system (65I cartridge,eluting with 45% to 55% ethyl acetate in hexane) to provide 5.17 g of2,2-dimethyl4-oxopentanenitrile as a pale yellow oil.

Part B

The methods described in Parts A through C of Example 64 were followed.In the final step, the product precipitated from the reaction mixtureand was isolated by filtration, washed with water, and dried on thevacuum filter funnel to provide 3.50 g of5-(2-cyano-2-methylpropyl)-1-propyl-1H-pyrazole-3-carboxamide as a whitesolid.

Anal. Calcd for C₁₂H₁₈N₄O: C, 61.52; H, 7.74; N, 23.91. Found: C, 61.31;H, 7.54; N, 24.18. The filtrate was concentrated and treated accordingto the work-up and purification procedures described in Part C ofExample 64.

Part C

The methods described in Parts D and E of Example 64 were used toconvert 5-(2-cyano-2-methylpropyl)-1-ethyl-1H-pyrazole-3-carboxamide(4.9 g, 20.9 mmol) into 5.88 g of4-bromo-5-(2-cyano-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile.Purification by IFC was carried out after each step.

Part D

A modification of the method described in Example 1283 was used tocouple4-bromo-5-(2-cyano-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile(1.48 g, 5.00 mmol) with 2-aminophenylboronic acid hydrochloride (1.73g, 10.0 mmol). The reaction was completed in one hour. The couplingproduct was purified by IFC (silica cartridge, eluting with 40% to 60%ethyl acetate in hexane). The reaction with hydrogen chloride was heatedat reflux for a total of about seven hours.3-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile(840 mg) was obtained as a white solid, mp 248-250° C.

MS (APCI) m/z 308 (M+H)⁺;

Anal. Calcd for C₁₈H₂₁N₅: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.18;H, 6.88; N, 23.02.

Example 12863-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanenitrile

Part A

The method described in Part A of Example 64 was used to convert2,2-dimethyl-4-oxopentanenitrile (8.19 g, 65.4 mmol) into 13.7 g ofethyl5-(2-cyano-2-methylpropyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate.

Part B

A solution of ethyl5-(2-cyano-2-methylpropyl)-1-(2-hydroxyethyl)-1H-pyrazole-3-carboxylate(6.12 g, 23.1 mmol) in THF (50 mL) was cooled to approximately 0° C.under nitrogen, and iodomethane (3.28 g, 23.1 mmol) was added. Sodiumhydride (0.924 g of 60% in mineral oil, 23.1 mmol) was added in oneportion. The mixture was allowed to warm to room temperature slowly andstirred overnight. Saturated aqueous ammonium chloride was added, andthe mixture was extracted three times with tert-butyl methyl ether. Thecombined extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide a yellow oil. The oil waspurified by chromatography on a HORIZON HPFC system (65I cartridge,eluting with ethyl acetate) to provide 3.68 g of ethyl5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylateas a pale yellow oil.

Part C

The methods described in Parts B and C of Example 64 were used to treatethyl5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate(3.66 g, 13.1 mmol). The final product was not purified bychromatography but was recrystallized from a mixture of 50% ethylacetate in hexane (100 mL) and ethyl acetate (35 mL). The crystals werewashed with 50% ethyl acetate in hexane and dried on the vacuum filterfunnel to provide 2.676 g of5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide,mp 130-131° C.

Anal. Calcd for C₁₂H₁₈N₄O₂: C, 57.58; H, 7.25; N, 22.38. Found: C,57.78; H, 6.92; N, 22.44.

Part D

The methods described in Parts D and E of Example 64 were used toconvert5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamideinto4-bromo-5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile.Purification by IFC was carried out after each step.

Part E

A modification of the method described in Part B of Example 1283 wasused to couple4-bromo-5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile(1.56 g, 5.00 mmol) with 2-aminophenylboronic acid hydrochloride (1.73g, 10.0 mmol). The reaction was completed in one hour. The couplingproduct was purified by IFC (silica cartridge, eluting with 50% to 90%ethyl acetate in hexane). The reaction with hydrogen chloride was heatedat reflux for two hours and allowed to cool to room temperatureovernight.3-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanenitrile(676 mg) was obtained as white crystals, mp 206-208° C.

MS (APCI) m/z 324 (M+H)⁺;

Anal. Cacld for C₁₈H₂₁N₅O: C, 66.85; H, 6.55; N, 21.66. Found: C, 66.81;H, 6.67; N, 21.82.

Example 12873-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanamide

3-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile(657 mg, 2.14 mmol), ethanol (10 mL), concentrated ammonium hydroxide(2.1 mL), and 30% w/w hydrogen peroxide (2.8 g) were combined in asealed glass tube and heated at 70° C. for seven hours. During thistime, the reaction was periodically cooled and the pressure released.Additional hydrogen peroxide (1.4 g) was added, and the reaction washeated at 70° C. for five hours, with periodic cooling and venting. Thereaction was cooled to 0° C., and water (25 mL) was added. A precipitateformed and was isolated by filtration, washed with water, purified bychromatography on a HORIZON HPFC instrument (40M cartridge), andrecrystallized from acetonitrile. The crystals were dried on the vacuumfilter funnel for two hours to provide 485 mg of3-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanamideas a white solid, mp 224-225° C.

MS (APCI) m/z 326 (M+H)⁺;

Anal. Calcd for C₁₈H₂₃N₅O.0.25 H₂O: C, 65.53; H, 7.18; N, 21.23. Found:C, 65.52; H, 7.30; N, 21.19.

Example 12883-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanamide

3-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanenitrile(436 mg, 1.35 mmol), ethanol (5 mL), sodium hydroxide (0.056 mL of 6 N),and 30% w/w hydrogen peroxide (0.54 mL, 4.7 mmol) were combined andheated at 50° C. for 18.5 hours. Water was added, and the ethanol wasremoved under reduced pressure. The mixture was extracted withchloroform, and the combined extracts were dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by IFC (silica cartridge) and recrystallized from 75% ethylacetate in hexane. The crystals were washed with 50% ethyl acetate inhexane, dried on the vacuum filter funnel overnight, and further driedunder vacuum at 9 Pa and 98° C. to provide3-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanamideas a white solid, mp 225-226° C.

MS (APCI) m/z 342 (M+H)⁺;

Anal. Calcd for C₁₈H₂₃N₅O₂: C, 63.32; H, 6.79; N, 20.51. Found: C,63.05; H, 6.86; N, 20.55.

Example 1289 1-(Aminomethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminehydrochloride

Part A

The method of Examples 1-4 Part A was followed to treat2-(2-oxopropyl)-1H-isoindole-1,3(2H)-dione (10.2 g, 50.0 mmol) with asolution of sodium tert-butoxide (5.77 g, 60.0 mmol) in ethanol (60 mL)and diethyl oxalate (8.77 g, 60.0 mmol). Ethyl5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dioxopentanoate sodiumsalt (14.00 g) was obtained as an orange solid.

Part B

The method described in Part B of Examples 1-4 was used to treat a 0° C.solution of the material from Part A (14.00 g, 43 mmol) in acetic acid(43 mL) with methylhydrazine (1.98 g, 43 mmol). During the addition overa period of ten minutes, the reaction temperature was maintained below15° C. The crude product was treated with 50% ethyl acetate in hexane toyield a powder. The solvents were removed under reduced pressure, andthe residue was recrystallized from ethanol to provide 8.13 g of ethyl5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylate.

Part C

A solution of ethyl5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylate(8.13 g, 25.9 mmol) in hydrochloric acid (33 mL of 1 M) and acetic acid(33 mL) was heated at reflux intermittently for six hours and allowed tocool to room temperature; a precipitate formed. Water was added, and thesolid was isolated by filtration, washed with water, and dried on thevacuum filter funnel for two days to provide 3.79 g of5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylicacid as a brown solid.

Part D

A solution of5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxylicacid (3.79 g, 13.3 mmol) and thionyl chloride (10 mL) in toluene (10 mL)was heated at 90° C. for 30 minutes under nitrogen and allowed to coolto ambient temperature. A precipitate formed upon cooling, and theprecipitate was isolated by filtration, washed with toluene, andsuspended in dichloromethane (40 mL). The suspension was poured intoconcentrated ammonium hydroxide (40 mL) that was cooled to 0° C. Thereaction was stirred for ten minutes. A precipitate formed and wasisolated by filtration, washed with water, and dried. The crude productwas purified by chromatography on a HORIZON HPFC system (40M cartridge)to provide 1.67 g of5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxamideas an off-white solid.

Part E

A solution of trifluoroacetic anhydride (0.996 mL, 7.05 mmol) indichloromethane (15 mL) was added slowly to a 0° C. solution of5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carboxamide(1.67 g, 5.87 mmol) and triethylamine (1.78 g, 17.6 mmol) indichloromethane (15 mL). The resulting solution was stirred for 30minutes, and water (50 mL) was added. The work-up procedure described inPart D of Example 64 was followed. Hexane (100 mL) was added to theresulting off-white solid, which was isolated by filtration and washedwith hexane. The resulting light-brown solid was purified bychromatography using a HORIZON HPFC system (40M cartridge, eluting with1% to 10% CMA in chloroform) to provide 1.57 g of5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrileas an off-white solid.

Part F

5-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile(1.57 g, 5.90 mmol) was brominated using a modified version of themethod described in Part F of Examples 14. In the reaction, 1.4equivalents of bromine were used instead of 1.1 equivalents. After thereaction was stirred for two days, additional potassium acetate (1.31 g)and bromine (0.211 mL) were added, and the reaction was stirred for fivemore days. After the addition of sodium hydrogensulfate, most of theacetic acid was removed under reduced pressure, and 2 M aqueous sodiumcarbonate was added. A solid formed and was isolated by filtration,washed with water, and dried on the vacuum filter funnel to provide 1.85g of4-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrileas a white solid.

Part G

The method described in Part F of Example 23 was followed using4-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile(1.85 g, 5.36 mmol) as the starting material with the modification thatdichloromethane (25 mL) was used as the solvent for the reaction withdi-tert-butyl dicarbonate (1.75 g, 8.00 mmol); this reaction was stirredovernight and filtered to remove a solid. The filtrate was concentratedunder reduced pressure and purified by IFC to provide 1.438 g oftert-butyl (4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)methylcarbamate asa white solid.

Part H

A modification of the method described in Example 1283 was used tocouple tert-butyl(4-bromo-3-cyano-1-methyl-1H-pyrazol-5-yl)methylcarbamate (1.43 g, 4.53mmol) with 2-aminophenylboronic acid hydrochloride (1.57 g, 9.06 mmol).The reaction was completed in 70 minutes. tert-Butyl methyl ether wasused instead of chloroform in the work-up procedure. The couplingproduct was purified by IFC (silica cartridge, eluting with 40% to 60%ethyl acetate in hexane). The reaction with hydrogen chloride was heatedat reflux for 24 hours. Diethyl ether (50 mL) was added after thereaction cooled to room temperature. A precipitate was present and wasisolated by filtration and dried on the vacuum filter funnel for threehours to provide 1.13 g of1-(aminomethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-aminehydrochloride as a white solid, mp >250° C.

MS (APCI) m/z 228 (M+H)⁺;

Anal. Calcd for C₁₂H₁₃N₅.0.2HCl.0.20H₂O: C, 47.44; H, 5.11; N, 23.06.Found: C, 47.80; H, 4.90; N, 22.68.

Example 12901-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

Part A

The method described in Part A of Example 1258 was followed on a 0.215mmol scale using propylhydrazine (35.3 g, 0.215 mmol) instead ofbutylhydrazine oxalate. After propylhydrazine was added, the reactionwas stirred for one hour. The chromatographic purification was carriedout on silica gel (eluting with 40% to 50% ethyl acetate in hexane) toprovide 15 g of ethyl5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carboxylate as abrown oil.

Part B

The methods described in Parts D and E of Example 60 were used toconvert ethyl5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carboxylate (14.4 g,56.6 mmol) to 10 g of5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carboxamide as anoff-white powder. After the saponification in Part D, the product wasobtained as an oil after extraction of the acidified solution withdichloromethane.

Part C

A modification of the method described in Part C of Example 1253 wasused to treat5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carboxamide (9.5 g,42.2 mmol) with trifluoroacetic anhydride (10.6 g, 50.6 mmol) in thepresence of triethylamine (12.8 g, 127 mmol). After the reaction wasstirred for one hour, additional trifluoroacetic anhydride (3 mL) wasadded to drive the reaction to completion. The resulting product wasbrominated according to the method described in Part F of Examples 1-4to provide 2-(4-bromo-1-butyl-3-cyano-1H-pyrazol-5-yl)-1,1-dimethylethyltrifluoroacetate as a brown oil.

Part D

A modification of the method described in Part C of Example 1258 wasused to treat the trifluoroacetate from Part C with potassium carbonate.Chloroform was used in the work-up procedure, and the final product waspurified by column chromatography on silica gel (eluting with 30% ethylacetate in hexane) to provide 5.5 g of4-bromo-5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile.

Part E

The methods described in Parts H and I of Example 60 were followed using5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile (2.75g, 9.61 mmol) as the starting material with the following modifications.Chloroform was used instead of dichloromethane in the extraction at theend of Part I. Following purification by column chromatography, theproduct was recrystallized from ethyl acetate. The crystals wereisolated by filtration, washed with ethyl acetate, and dried undervacuum at 65° C. for four hours to yield 1.2 g of1-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas off-white crystals, mp 188-190° C.

MS (APCI) m/z 299 (M+H)⁺;

Anal. Calcd for C₁₇H₂₂N₄O:C, 68.43; H, 7.43: N, 18.78. Found: C, 68.16;H, 7.34; N, 18.67.

Example 12911-(4-Amino-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol

A modification of the method described in Example 61 was followed using1-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol(0.65 g, 2.18 mmol) as the starting material. The hydrogenation wasrepeated after the product obtained after chromatographic purificationof the first reaction mixture (silica gel, eluting with 5% methanol indichloromethane) yielded mostly starting material. The product obtainedafter the second hydrogenation (0.27 g) was recrystallized from ethylacetate (5 mL) to provide1-(4-amino-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-olas white crystals, mp 143-145° C.

MS (ESI) m/z 303 (M+H)⁺;

Anal. Cacld for C₁₇H₂₆N₄O:C, 67.52; H, 8.67: N, 18.53. Found: C, 67.21;H, 8.85; N, 18.58.

Example 1292 1-{2-Methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

A solution of4-bromo-5-(2-hydroxy-2-methylpropyl)-1-propyl-1H-pyrazole-3-carbonitrile(2.7 g, 9.43 mmol) in THF (38 mL) was purged with nitrogen, and sodiumhydride (37 mg of a 60% dispersion in mineral oil) was added. Thereaction was stirred for five minutes, and methyl vinyl sulfone (2.0 g,19 mmol) was added. The reaction was stirred at room temperature for 18hours, and additional sodium hydride (0.11 g) was added. The reactionwas stirred for one hour, and additional sodium hydride (0.07 g) wasadded. The reaction was stirred for one hour, and a few drops of waterwere added. The mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (elutingwith 50% to 60% ethyl acetate in hexane) to provide 2 g of mixture of4-bromo-5-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1-propyl-1H-pyrazole-3-carbonitrileand methyl vinyl sulfone.

Part B

The methods described in Parts H and I of Example 60 were followed usingthe material from Part A as the starting material with the followingmodifications. Chloroform was used instead of dichloromethane in theextraction at the end of Part I. Following purification by columnchromatography, the product was recrystallized from acetonitrile. Thecrystals were isolated by filtration, washed with acetonitrile, anddried under vacuum at 65° C. for four hours to yield 0.6 g of1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 197-200° C.

MS (APCI) m/z 405 (M+H)⁺;

Anal. Cacld for C₂₀H₂₈N₄O₃S: C, 59.38; H, 6.98: N, 13.85. Found: C,59.07; H, 6.68; N, 13.78.

Example 12932-Ethyl-1-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Hydrogen chloride (21 mL of a 3.6 M solution in ethanol) was added to asolution of tert-butyl2-(4-bromo-3-cyano-1-ethyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate(5.6 g, 15 mmol), prepared in Example 1244, in ethanol (75 mL), and thereaction was stirred at room temperature for two days and concentratedunder reduced pressure. The residue was suspended in water (50 mL), andaqueous sodium hydroxide (50% w/w) was added to adjust the mixture to pH12. The basic mixture was extracted with dichloromethane (2×50 mL), andthe combined extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide 4.1 g of5-(2-amino-2-methylpropyl)-4-bromo-1-ethyl-1H-pyrazole-3-carbonitrile asa colorless oil.

Part B

A solution of5-(2-amino-2-methylpropyl)4-bromo-1-ethyl-1H-pyrazole-3-carbonitrile(4.1 g, 15.1 mmol) and methyl vinyl sulfone (3.2 g, 30.2 mmol) intoluene (30 mL) was heated at reflux for 15 hours, allowed to cool toroom temperature, and concentrated under reduced pressure. The crudeproduct was purified twice by column chromatography on silica gel(eluting first with 5% methanol in dichloromethane and secondly withethyl acetate) to provide 2.75 g of4-bromo-1-ethyl-5-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-1H-pyrazole-3-carbonitrileas a colorless oil.

Part C

The methods described in Parts F and G of Example 1255 were followedusing4-bromo-1-ethyl-5-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-1H-pyrazole-3-carbonitrile(2.75 g, 7.29 mmol) as the starting material with the followingmodifications. The reaction with hydrogen chloride was stirred overnightat room temperature and then heated at reflux for eight hours. Followingthe work-up procedure, a brown oil was isolated and was purified bycolumn chromatography on silica gel (eluting with 5% methanol indichloromethane) followed by recrystallization from butyl acetate (10mL). The crystals were isolated by filtration, washed with butylacetate, and dried under vacuum at 65° C. for 14 hours to yield 0.8 g of2-ethyl-1-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 155-157° C.

MS (APCI) m/z 405 (M+H)⁺;

Anal. Cacld for Cl₉H₂₇N₅O₂S: C, 58.59; H, 6.99: N, 17.98. Found: C,58.41; H, 7.00; N, 18.13.

Example 12941-[2-Methyl-2-(methylsulfonyl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

The method described in Part B of Example 60 was followed using4-methyl-4-(methylthio)pentan-2-one (10.0 g, 68.4 mmol) instead of4-(propylthio)butan-2-one and propylhydrazine (11.2 g, 68.4 mmol)instead of butylhydrazine with the modification that the reaction withsodium tert-butoxide (6.6 g, 68 mmol) was stirred for one hour.Propylhydrazine was added at room temperature. Following chromatographicpurification, 10.6 g of ethyl5-[2-methyl-2-(methylthio)propyl]-1-propyl-1H-pyrazole-3-carboxylatewere obtained and was treated with mCPBA (15 g of 60% pure material)according to the method of Part C of Example 60 to provide 9.4 g ofethyl5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxylate.

Part B

A pressure vessel containing ethyl5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxylate(9.4 g, 29.7 mmol) and ammonia (50 mL of a 7 N solution in methanol),and the vessel was sealed and heated at 150° C. for 41 hours and allowedto cool to room temperature. The volatiles were removed under reducedpressure to provide 8.5 g of5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxamideas a brown oil.

Part C

A modification of the method described in Part C of Example 1253 wasused to treat5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxamide(8.5 g, 29.7 mmol) with trifluoroacetic anhydride (7.5 g, 35.6 mmol) inthe presence of triethylamine (9 g, 90 mmol). After the reaction wasstirred for one hour, additional trifluoroacetic anhydride (2.5 mL) wasadded to drive the reaction to completion. The resulting product wasbrominated according to the method described in Part F of Examples 1-4to provide4-bromo-5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carbonitrileas a colorless oil.

Part D

The methods described in Parts F and G of Example 1255 were followedusing4-bromo-5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carbonitrile(5.8 g, 17 mmol) as the starting material with the followingmodifications. Following the work-up procedure, an oil was isolated andwas purified by column chromatography on silica gel (eluting with 5%methanol in dichloromethane) followed by recrystallization from ethanol(32 mL). The crystals were isolated by filtration, washed with ethanol,and dried under vacuum at 65° C. for 17 hours to yield 1.1 g of1-[2-methyl-2-(methylsulfonyl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 202-204° C.

MS (APCI) m/z 361 (M+H)⁺;

Anal. Cacld for C₁₈H₂₄N₄O₂S: C, 59.97; H, 6.71: N, 15.54. Found: C,60.07; H, 6.38; N, 15.52.

Example 12951-[2-Methyl-2-(methylsulfonyl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

A modification of the method described in Example 61 was followed using1-[2-methyl-2-(methylsulfonyl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(0.45 g, 1.25 mmol) as the starting material. The crude product (0.4 g)was purified by column chromatography on silica gel (eluting with 5%methanol in dichloromethane) followed by recrystallization from ethanol(6 mL). The crystals were isolated by filtration, washed with ethanol,and dried under vacuum at 65° C. for four hours to yield 0.1 g of1-[2-methyl-2-(methylsulfonyl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas white crystals, mp 209-211° C.

Anal. Cacld for C₁₈H₂₈N₄O₂S: C, 59.31; H, 7.74: N, 15.37. Found: C,59.17; H, 7.51; N, 15.65.

Examples 1296-1297

A mixture of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (preparedas described in Parts A and B of Example 15, 2.0 equivalents) in I-propanol (20 mL) and 1 M aqueous HCl (15 mL) was heated at 80° C. for90 minutes. The reaction was allowed to cool to room temperature andsolid sodium carbonate (1.5 equivalents) was added with stirring. A4-bromo-1,5-disubstitued-1H-pyrazole-3-carbonitrile (3.3-3.5 g, 14 mmol,1 equivalent) shown in the table below,bis(2-diphenylphosphinophenyl)ether (0.05 equivalent), and palladium(II) acetate (0.05 equivalent) were added. The reaction and work-upprocedures were carried out as described in Examples 52 through 55. Thecrude product was purified by chromatography on a HORIZON HPFC system(silica gel, gradient elution using 0-40% CMA in chloroform) followed byrecrystallization from the solvent shown in the table below. Crystalswere isolated, washed with cold solvent, and dried overnight at 60° C.in a vacuum oven to provide the product.

Example 1296

1-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2-methylpropan-2-ol was isolated as whiteneedles, mp 283-286° C.

Anal. calcd for C₁₅H₁₉N₅O.0.4 H₂O: C, 61.60; H1 6.82; N, 23.94. Found:C, 61.77; H, 6.75; N, 23.96.

Example 1297

1-(4-Amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2-methylpropan-2-ol was isolated as whiteneedles, mp 252-255° C.

Anal. calcd for C₁₆H₂₁N₅O: C, 64.19; H, 7.07; N, 23.39. Found: C, 63.88;H, 7.23; N, 23.25.

Examples 1296-1297

Recrystallization Example Starting Material solvent R₂ 12964-Bromo-1-ethyl-5-(2-hydroxy-2- acetonitrile —CH₂CH₃methylpropyl)-1H-pyrazole-3-carbonitrile (Example 62 Parts A-F) 12974-Bromo-5-ethyl-1-propyl-1H-pyrazole-3- 2-propanol —CH₂CH₂CH₃carbonitrile (Example 1290 Parts A-D)

Examples 1298-1300

A mixture of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (preparedas described in Parts A and B of Example 15, 2.0 equivalents) and 1 Maqueous was heated at 80° C. for 45 minutes. The reaction was allowed tocool to room temperature and solid sodium carbonate (3.3equivalents) wasadded with stirring. A4-bromo-1,5-disubstitued-1H-pyrazole-3-carbonitrile (1 equivalent) shownin the table below, DME, anddichlorobis(triphenylphosphine)palladium(II) (0.05 equivalent)wereadded. The reaction and work-up procedures were carried out as describedin Examples 52 through 55. The crude product was purified bychromatography on a HORIZON HPFC system (silica gel, gradient elutionusing CMA in chloroform) followed by recrystallization from the solventindicated below. Crystals were isolated, washed with cold solvent, anddried overnight at 60° C. in a vacuum oven to provide the product.

Example 1298

Recrystallization was carried out with acetonitrile to provide1-(4-amino-2-butyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2-methylpropan-2-olas white needles, mp 232-235° C.

Anal. calcd for C₁₇H₂₃N₅O: C, 65.15; H, 7.40; N, 22.35. Found: C, 64.97;H, 7.59; N, 22.63.

Example 1299

Recrystallization was carried out with propyl acetate to provide3-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2,2-dimethylpropanenitrileas white needles, mp 249-252° C.

Anal. calcd for C₁₇H₂₀N₆: C, 66.21; H, 6.54; N, 27.25. Found: C, 66.15;H, 6.43; N, 27.41.

Example 1300

Recrystallization was carried out with acetonitrile to provide1-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl]-2-methylpropan-2-olas light yellow needles, mp 233-236° C.

Anal. calcd for C₁₆H₂₁N₅O₂: C, 60.94; H, 6.71; N, 22.21. Found: C,60.64; H, 6.72; N, 22.20.

Examples 1298-1300

Example Starting Material R₁ R₂ 1298 4-Bromo-1-butyl-5-(2-hydroxy-2-—CH₂C(CH₃)₂OH —CH₂CH₂CH₂CH₃ methylpropyl)-1H-pyrazole-3-carbonitrile(Example 1258 Parts A-D) 1299 4-Bromo-5-(2-cyano-2-methylpropyl)-1-—CH₂C(CH₃)₂CN —CH₂CH₂OCH₃ propyl-1H-pyrazole-3-carbonitrile (Example1285 Parts A-C) 1300 4-Bromo-5-(2-hydroxy-2-methylpropyl)- —CH₂C(CH₃)₂OH—CH₂CH₂CH₃ 1-(2-methoxyethyl)-1H-pyrazole-3- carbonitrile (Example 1260Parts A-D)

Example 13013-(4-Amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2,2-dimethylpropanamide

Hydrogen peroxide (0.8 mL of 30%) was added to a suspension of3-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2,2-dimethylpropanenitrile(0.54 g, 1.75 mmol) in 6 N aqueous sodium hydroxide. The reaction andwork-up procedures described in Example 1288 were followed with themodification that the reaction was heated for 5.5 hours. Followingchromatographic purification (eluting with 0% to 55% CMA in chloroform)and drying under high vacuum, 0.16 g of3-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,8]naphthyridin-1-yl)-2,2-dimethylpropanamidewas obtained as a white solid, mp 254-257° C.

Anal. calcd for C₁₇H₂₂N₆O: 0.1 H₂O: C, 62.21; H, 6.82; N, 25.61. Found:C, 62.01; H, 7.09; N, 25.54.

Example 13023-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]-1,8-naphthyridin-1-yl]-2,2-dimethylpropanamide

The method of Examples 1298-1300 and the method of Example 1301 wereused to convert4-bromo-5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrileto3-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]-1,8-naphthyridin-1-yl]-2,2-dimethylpropanamide.Following chromatographic purification the product was recrystallizedfrom acetonitrile to provide3-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]-1,8-naphthyridin-1-yl]-2,2-dimethylpropanamideas a white solid, mp 254-257° C. ¹H NMR (500 MHz, d₆-DMSO) δ 8.50 (dd,J=7.9, 1.9, 1H), 8.46 (dd, J=4.4, 1.6, 1H), 7.14 (dd, J=7.9, 4.4, 1H),7.15-7.00 (m, 4H), 4.56 (t, J=4.4, 2H), 3.77 (t, J=5.10, 2H), 3.50 (s,2H), 3.18 (s, 3H), 1.12 (s, 6H); ¹³C NMR (125 MHz, d₆-DMSO) δ 178.3,154.9, 153.0, 147.1, 136.9, 135.5, 130.5, 117.7, 116.5, 114.3, 71.0,58.3, 50.0, 43.9, 33.6, 24.8; HRMS (EI) calcd for C₁₇H₂₂N₆O₂ 343.1882,found 343.1886.

Example 13034-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-N,N-dimethylbutane-1-sulfonamide

Part A

Potassium thioacetate (595 mg, 5.20 mmol) was added to a solution of1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 46) (1.50 g, 4.73 mmol) in DMF (24 mL) atambient temperature. The reaction mixture was stirred for 24 hours andbecame a light yellow and cloudy mixture. The reaction mixture wasconcentrated under reduced pressure, diluted with methylene chloride(200 mL), and washed with water (75 mL), and the resulting layers wereseparated. The aqueous layer was extracted with methylene chloride (50mL). The combined organic layers were dried over magnesium sulfate andconcentrated under reduced pressure to yield 1.92 g of a tan material.

Part B

The material from part A (1.92 g) was dissolved in methanol (47 mL) anddegassed with nitrogen for several minutes at ambient temperature.Sodium methoxide in methanol solution (1.20 mL, 25 wt % in MeOH) wasadded to the reaction mixture, followed by degassing with nitrogen.After 1 hour, 7M HCl (0.9 mL) was added to the reaction mixture andstirred for a few minutes. The reaction mixture was concentrated underreduced pressure, diluted with methylene chloride (80 mL), washed withwater (75 mL), and the resulting layers were separated. The aqueouslayer was extracted with methylene chloride (50 mL). The combinedorganic layers were dried over magnesium sulfate and concentrated underreduced pressure to yield 1.37 g of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol as alight yellow solid.

Part C

Water (0.2 mL) was added to a suspension of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol (1.37g, 4.36 mmol) in dichloromethane (22 mL) maintained at 0° C. In aseparate container, trichloroisocyanuric acid (1.11 g, 4.80 mmol) andbenzyltrimethylammonium chloride (2.75 g, 14.8 mmol) were added atambient temperature to dichloromethane (22 mL), stirred for 45 minutes,and the resulting solution was added dropwise to the reaction mixturecontaining4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol over2 minutes. After 25 minutes, dimethylamine hydrochloride (1.55 g, 13.1mmol) was added to the reaction mixture. Potassium carbonate (6M, 44 mL)was added to the reaction mixture with vigorous stirring over 2 minutesat ambient temperature. The reaction mixture was stirred for 2 hours andpotassium carbonate (6M, 0.5 mL) was added and the mixture wasmaintained for an additional hour. The reaction mixture was diluted withmethylene chloride (250 mL), washed with water (200 mL, pH 10), and theresulting layers were separated. The organic layer was dried overmagnesium sulfate and concentrated under reduced pressure to provide1.13 g of a tan foam. The resulting material was purified by columnchromatography on a HORIZON HPFC system (eluting with methanol and ethylacetate) to provide 460 mg of a white foam. The material was dissolvedand triturated from acetonitrile, and dried under reduced pressure toyield 146 mg of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-N,N-dimethylbutane-1-sulfonamideas a white solid, mp 144-146° C.

MS (El) m/z 390 (M+H)⁺;

Anal. calcd for C₁₉H₂₇N₅O₂S: C, 58.59; H, 6.99; N, 17.98. Found: C,58.53; H, 7.13; N, 18.04.

Example 13044-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-N-methylbutane-1-sulfonamide

Water (0.10 mL) was added to a suspension of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol (1.37g, 4.36 mmol) (prepared as described in Part B of Example 1303) indichloromethane (24 mL) maintained at 0° C. In a separate container,trichloroisocyanuric acid (600 mg, 2.58 mmol) and benzytrimethylammoniumchloride (1.48 g, 8.0 mmol) were added at ambient temperature todichloromethane (12 mL), stirred for 45 minutes, and the resultingsolution was added dropwise to the reaction mixture containing4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol over2 minutes. After 30 minutes, methylamine hydrochloride (475 mg, 7.0mmol) was added to the reaction mixture. Potassium carbonate (6M, 1.6mL) was added to the reaction mixture with vigorous stirring over 2.5hours at ambient temperature. The reaction mixture was diluted withmethylene chloride (300 mL), washed with water (300 mL), and theresulting layers were separated. The aqueous layer was extracted withdichloromethane (2×300 mL) and the combined organic layers were driedover magnesium sulfate and concentrated under reduced pressure toprovide 0.65 g of foam. The resulting material was purified by columnchromatography on a HORIZON HPFC system (eluting with CMA:chloroformranging in ratios from 0:100 to 20:80) to provide 190 mg of material.The material was recrystallized from isopropanol, dried in a vacuumoven, recrystallized from acetonitrile and dried in a vacuum oven toyield 88 mg of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-N-methylbutane-1-sulfonamideas a light yellow solid, mp 166-169° C. MS (EI) m/z 376 (M+H)⁺;

Anal. calcd for C₁₈H₂₅N₅O₂S.0.02 CH₃CN: C, 57.58; H, 6.71; N, 18.68.Found: C, 57.49; H, 6.85; N, 19.01.

Example 13054-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-sulfonamide

Part A

A suspension of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol (1.37g, 4.36 mmol) (prepared as described in Part B of Example 1303) indichloromethane (24 mL) was maintained at 0° C. In a separate container,trichloroisocyanuric acid (632g, 2.72 mol) and benzytrimethylammoniumchloride (1.56 g, 8.4 mmol) were added at ambient temperature todichloromethane (12 mL), stirred for 45 minutes, and the resultingsolution was added dropwise to the reaction mixture containing4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-thiol over2 minutes. Water (0.09 mL) was then added to the red solution. Afterabout 1 hour, 4-methoxybenzylamine (2.10 mL, 16.0 mmol) was added to thereaction mixture, which was maintained for 15 hours at ambienttemperature. The reaction mixture was diluted with methylene chloride(225 mL) and water (300 mL), and the resulting layers were separated.The aqueous layer was extracted with dichloromethane (3×100 mL) and thecombined organic layers were washed with water (100 mL), dried overmagnesium sulfate, and concentrated under reduced pressure to provide1.8 g of material. The resulting material was suspended in chloroform(20 mL) and filtered. The filtrate was purified by column chromatographyon a HORIZON HPFC system (eluting with CMA:chloroform ranging in ratiosfrom 0:100 to 15:85) to provide 420 mg of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-N-(4-methoxybenzyl)-butane-1-sulfonamide.

Part B

Anisole (108 μL, 1.0 mmol) was added to a solution of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-N-(4-methoxybenzyl)-butane-1-sulfonamide(400 mg, 0.83 mmol) in trifluoroacetic acid (8 mL) at ambienttemperature and stirred for 3.5 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in dichloromethane,washed with saturated aqueous sodium bicarbonate, and the layers wereseparated. The organic layer was diluted with methanol (5-7 mL), driedover magnesium sulfate, and concentrated under reduced pressure toafford 420 mg of material. The material was triturated with ethylacetate (12 mL) to afford 234 mg of material. The material was thentriturated with hot ethyl acetate, recrystallized from methanol (10 mL)and dried in a vacuum oven to provide 155 mg of colorless crystals. Thematerial was adsorbed onto silica gel and purified by columnchromatography on a HORIZON HPFC system (eluting with CMA:chloroformranging in ratios from 0:100 to 30:70) and dried in a vacuum oven toyield 128 mg of4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butane-1-sulfonamideas a white solid, mp 211-213° C.

MS (El) m/z 362 (M+H)⁺;

Anal. calcd for C₁₇H₂₃N₅O₂S: C, 56.49; H, 6.41; N, 19.37. Found: C,56.48; H, 6.56; N, 19.40.

Example 1306(1E,Z)-4-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butanal oxime

Part A

Hydroxylamine hydrochloride (1.9 g, 27.4 mmol) was added to a solutionof di(tert-butyl)1-(4-oxobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(12.39 g, 24.95 mmol) (prepared as described in Parts A through D ofExample 57) in ethanol (300 mL) and water (200 mL). A 50% w/w solutionof aqueous sodium hydroxide (3 mL) was added to the reaction mixture andstirred for 30 minutes. The reaction mixture was partitioned betweenwater and dichloromethane and the phases were separated. The aqueousphase was extracted with dichloromethane and the combined organic phaseswere washed with water, washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to afford 11.2 g of adark yellow solid. The material was purified via column chromatographyover silica gel eluting with hexane and ethyl acetate. The material wasthen triturated with ether to obtain 5.9 g of a white powder and used asis for subsequent reactions.

Part B

6 N Hydrochloric acid solution (4 mL) was added to the material obtainedfrom Part A (0.75 g, 1.466 mmol) and stirred at ambient temperature for3.5 hours. The reaction mixture was concentrated under reduced pressureand partitioned between 1 N potassium hydroxide solution anddichloromethane. The organic layer was washed with water, washed withbrine, dried over potassium carbonate, filtered, and concentrated toafford 0.4458 g of amber oil. The material was purified via columnchromatography over silica gel (60 g) eluting with CMA:chloroform in a10:90 ratio to provide 0.1405 g of material. The material was trituratedwith ether, filtered, and dried at 70° C. for 18 hours to yield 0.0771 gof (1E,Z)4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butanaloxime as a white powder, mp 211-213° C.

MS (APCI) m/z 312 (M+H)⁺;

Anal. calcd for C₁₇H₂₁N₅O: C, 65.57; H, 6.80; N, 22.49. Found: C, 65.12;H, 7.08; N, 22.36.

Example 13071-[3-(5-Phenylisoxazol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

N-Chlorosuccinimide (0.33 g, 2.47 mmol) was added to a solution of thematerial from Part A of Example 1306 (1.15 g, 2.25 mmol) in DMF andheated to 50° C. for 2.5 hours. Phenylacetylene (0.5 mL, 4.50 mmol) andanhydrous triethylamine (0.8 mL, 5.62 mmol) were then added to thereaction mixture and heated for an additional hour. The reaction mixturewas concentrated under reduced pressure, dissolved in ethyl acetate,washed with water, washed with brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The material waspurified via column chromatography over silica gel eluting with hexaneand ethyl acetate and concentrated under reduced pressure to yield 0.70g of material and used as is for subsequent reactions.

Part B

6 M Hydrochloric acid solution in ethanol (20 mL) was added to thematerial obtained from Part A (0.70 g, 1.144 mmol) and stirred atambient temperature for 1 hour, heated to 50° C. for 6 hours andmaintained overnight at ambient temperature. The reaction mixture wasconcentrated under reduced pressure. Water was added to the residue andthe pH of the water was adjusted to 14 with dropwise addition of 50%sodium hydroxide solution. Material precipitated out of the solution andwas filtered and collected. The precipitate was triturated with etherand dried under reduced pressure at 80° C. for 22 hours to yield 0.3982g of1-[3-(5-phenylisoxazol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 172-173° C.

MS (APCI) m/z 412 (M+H)⁺;

Anal. calcd for C₂₅H₂₅N₅O.0.3H₂O: C, 72.02; H, 6.19; N, 16.80. Found: C,71.83; H, 6.42; N, 16.81.

Example 13081-[3-(5-Butylisoxazol-3-yl)propyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

N-Chlorosuccinimide (0.38 g, 2.82 mmol) was added to a solution of thematerial from Part A of Example 1306 (1.31 g, 2.56 mmol) in DMF andheated to 50° C. for 2 hours. 1-Hexyne (0.6 mL, 5.12 mmol) and anhydroustriethylamine (0.9 mL, 6.40 mmol) were then added to the reactionmixture and heated for an additional hour. The reaction mixture wasdiluted with water (200 mL) and extracted with ethyl acetate severaltimes. The combined organic layers were washed with water, washed withbrine, dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The material was purified via column chromatographyover silica gel (60 g) eluting with hexane and ethyl acetate andconcentrated under reduced pressure to afford 0.44 g of material andused as is for subsequent reactions.

Part B

6 M Hydrochloric acid solution in ethanol (20 mL) was added to thematerial obtained from Part A (0.44 g, 0.7435 mmol) and stirred at 25°C. for 16 hours. The reaction mixture was concentrated under reducedpressure. Water was added to the residue and the pH of the water wasadjusted to 14 with dropwise addition of 50% sodium hydroxide solutionand stirred for 1 hour at ambient temperature. Material precipitated outof the solution and was filtered and collected. The precipitate wasdried under reduced pressure at 85° C. for 18 hours to yield 0.2852 g of1-[3-(5-butylisoxazol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a tan powder, mp 132-133° C.

MS (APCI) m/z 392 (M+H)⁺;

Anal. calcd for C₂₂H₂₉N₅O.0.3H₂O: C, 69.60; H, 7.52; N, 17.64. Found: C,69.52; H, 7.22; N, 17.74.

Example 13092-Propyl-1-[3-(5-pyridin-3-ylisoxazol-3-yl)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

N-Chlorosuccinimide (0.33 g, 2.47 mmol) was added to a solution of thematerial from Part A of Example 1305 (1.15 g, 2.25 mmol) in DMF andheated to 50° C. for 1.7 hours. 3-Ethynylpyridine (0.46 g, 4.50 mmol)and anhydrous triethylamine (0.8 mL, 5.62 mmol) were then added to thereaction mixture and heated for an additional hour. The reaction mixturewas concentrated under reduced pressure, diluted with dichloromethane,washed sequentially with potassium carbonate solution, water, and brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The material was purified via column chromatography oversilica gel (60 g) eluting with hexane and ethyl acetate and concentratedunder reduced pressure to afford 0.77 g of material and used as is forsubsequent reactions.

Part B

6 M Hydrochloric acid solution in ethanol (20 mL) was added to thematerial obtained from Part A (0.77 g, 1.257 mmol) and stirred at 50° C.for 1.7 hours. The reaction mixture was concentrated under reducedpressure. Water was added to the residue and the pH of the water wasadjusted to 14 with dropwise addition of 50% sodium hydroxide solutionand stirred for 45 minutes at ambient temperature. Material precipitatedout of the solution and was filtered and collected. The precipitate wastriturated with ether, then purified via column chromatography oversilica gel (60 g eluting with CMA in chloroform in a ratio ranging from1:99 to 10:90) to yield 0.1638 g of2-propyl-1-[3-(5-pyridin-3-ylisoxazol-3-yl)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amineas a white crystalline solid, mp 196-198° C.

MS (APCI) m/z 413 (M+H)⁺;

Anal. calcd for C₂₄H₂₄N₆O.0.5CH₄O: C, 68.75; H, 6.01; N, 19.64. Found:C, 68.58; H, 6.11; N, 19.97.

Example 1310(1E,Z)-4-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butanalO-methyloxime

Part A

O-Methyl hydroxylamine hydrochloride (0.18 g, 2.10 mmol) was added to asolution of di(tert-butyl)1-(4-oxobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(0.9462 g, 1.90 mmol) (prepared as described in Parts A through D ofExample 57) in ethanol (6 mL) and water (4 mL). A 50% w/w solution ofaqueous sodium hydroxide (1 mL) was added to the reaction mixture andstirred for 30 minutes. The reaction mixture was partitioned betweenwater and dichloromethane and the phases were separated. The organicphase was washed with brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford 0.84 g of a dark ambersolid. The material was used as is for subsequent reactions.

Part B

6 N Hydrochloric acid solution in ethanol (10 mL) was added to thematerial obtained from Part A (0.84 g, 1.59 mmol) and stirred at ambienttemperature for 4 hours, 50° C. for 1.5 hours, and ambient temperaturefor 18 hours. The reaction mixture was diluted with water and the pH wasadjusted to 14 with dropwise addition of 50% sodium hydroxide solutionand material oiled out of solution. The aqueous layer was extracted withdichloromethane and the combined organic layers were washed with water,washed with brine, dried over sodium sulfate, filtered, and concentratedto afford 0.450 g of an amber oil. The material was purified via columnchromatography over silica gel (40 g) eluting with 1% CMA in chloroformand recrystallized for hexane/ethyl acetate. The material was furtherpurified via column chromatography over silica gel (40 g) eluting with1% methanol in ethyl acetate and recrystallized for hexane/ethyl acetateto provide 0.032 g of(1E,Z)-4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butanalO-methyloxime as a white crystalline solid, mp 117-119° C.;

MS (APCI) m/z 326 (M+H)⁺;

Anal. calcd for C₁₈H₂₃N₅O: C, 66.44; H, 7.12; N, 21.52. Found: C, 66.57;H, 7.40; N, 21.43.

Example 13111-[3-(1-Benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Benzylamine (51.5 g, 480 mmol) was added to(chloromethyl)trimethylsilane (19.64 g, 160 mmol) and heated at 200° C.for 2 hours. The reaction mixture was diluted with 1 N sodium hydroxidesolution and ether and the organic layer was dried over magnesiumsulfate and concentrated under reduced pressure. The residue wasdistilled under reduced pressure to afford 23.00 g ofN-benzyl-N-trimethylsilanylmethyl-amine.

Part B 1 N Hydrochloric acid solution (119 mL) was added toN-benzyl-N-trimethylsilanylmethyl-amine (23.00 g, 119 mmol) and whiteprecipitate formed. Tetrahydrofuran (650 mL), potassium cyanide (9.3 g,143 mmol), and aqueous formaldehyde solution (37 wt. %, 12 mL, 155 mmol)were added to the reaction mixture and stirred at ambient temperaturefor 15 hours. The mixture was extracted with ether and separated and thecombined organic layers were washed with water, dried over magnesiumsulfate, and concentrated sequentially under reduced pressure and highvacuum at ambient temperature to afford 27.80 g of(N-Benzyl-N-trimethylsilanylmethyl-amino)acetonitrile.

Part C

Di(tert-butyl)1-pent4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate(prepared as described in Parts A-E of Example 57) (6.40 g, 13.0 mmol),silver fluoride (3.6 g, 28.6 mmol), and acetonitrile (30 mL) were addedsequentially to a solution of(N-Benzyl-N-trimethylsilanylmethyl-amino)acetonitrile (6.6 g, 28.6 mmol)in acetonitrile (50 mL) and stirred at ambient temperature in the darkfor 22 hours. The reaction mixture was filtered through a bed ofactivated carbon and CELITE filter agent rinsed with dichloromethane toobtain 9.43 g of a yellow oil. The material was purified via columnchromatography over silica gel (40 g) eluting with ethyl acetate toprovide 4.7 g of product as a light amber solid and used as is insubsequent reactions.

Part D

6 N Hydrochloric acid in ethanol (75 mL, 75.1 mmol) was added to thematerial prepared in part C (4.7 g, 7.51 mmol) and stirred at ambienttemperature for 14 hours. The reaction mixture was concentrated underreduced pressure and diluted with water and the pH was adjusted to 14with dropwise addition of 50% sodium hydroxide solution. The aqueouslayer was extracted with dichloromethane and the combined organic layerswere washed sequentially with water and brine, dried over sodiumsulfate, filtered, and concentrated to afford 3.12 g of white solid. Thematerial was purified via recrystallization from isopropanol to obtain0.5868 g of1-[3-(l-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 150-152° C.

Anal. calcd for C₂₇H₃₁N₅: C, 76.20; H, 7.34; N, 16.46. Found: C, 75.95;H, 7.40; N, 16.45.

Example 13121-[3-(1-Benzyl-1H-pyrrol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine

2,3-Dichloro-5,6-dicyano-p-benzoquinone (1.13 g, 4.98 mmol) was added toa mixture of1-[3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl]-2-propyl-2H-pyrazolo[c]quinolin-4-amine(prepared as described in Example *S-35465) (2.12 g, 4.98 mmol) intoluene (60 mL) stirred and heated to 70° C. for 2.5 hours. The reactionmixture was cooled to ambient temperature, diluted with dichloromethane,and washed with potassium carbonate solution and the phases wereseparated. The aqueous layers were washed with chloroform and thecombined organic layers were washed sequentially with water and brine,dried over sodium sulfate, and filtered. The dried organic mixture wasfiltered through a bed of activated carbon with CELITE filter agent andrinsed with hot chloroform and concentrated under reduced pressure toprovide 0.556 g of brown oil. The material was purified via columnchromatography over silica gel (40 g) eluting with 2-10% CMA inchloroform, recrystallized from isopropanol, and dried under reducedpressure over 1 week to afford 0.2674 g of1-[3-(1-benzyl-1H-pyrrol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amineas a brown crystalline solid, mp 138-140° C.

MS (APCI) m/z 424 (M+H)⁺;

Anal. calcd for C₂₇H₂₉N₅: C, 76.56; H, 6.90; N, 16.53. Found: C, 76.34;H, 6.83; N, 16.41.

Example 13132-Propyl-1-[3-(1H-pyrrol-3-yl)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

1-[3-(1-Benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 1311) (0.475 g, 1.117 mmol) was addedto dioxane (10 mL) and heated at 70° C. open to the atmosphere for 21hours. The reaction mixture was concentrated under reduced pressure,dried under high vacuum for 18 hours, triturated with ether, andfiltered to afford 0.3916 g of material used as is in subsequentreactions.

Part B

Sodium metal (0.058 mg) was dissolved in a solution of liquid ammonia at−78° C. for several minutes and the solution became a dark blue color.The material from Part A (0.3916 g, 0.924 mmol) was added to thereaction mixture as a solution in THF (5 mL), and the mixture became adark red color within minutes. After 5 minutes and 15 minutes,additional sodium metal (0.015 g and 0.023 g, respectively) was added tothe reaction mixture and maintained at −78° C. for 1 hour as a light redsolution. Solid ammonium chloride was added to the reaction mixture andthe reaction mixture was warmed to ambient temperature. The resultingslurry was diluted with dichloromethane, washed sequentially with waterand brine, dried over magnesium sulfate, filtered, and concentrated anddried under reduced pressure to afford 0.32 g of a yellow oil. Thematerial was purified via column chromatography over silica gel (10 g)eluting with 2-5% CMA in chloroform, and concentrated under reducedpressure for 1 week to yield 0.1103 g of2-propyl-1-[3-(1H-pyrrol-3-yl)propyl]-2H-pyrazolo[3,4-c]quinolin-4-amineas a tan powder, mp 173-174° C.

MS (APCI) m/z 334 (M+H)⁺;

Anal. calcd for C₂₀H₂₃N₅.0.5 H₂O: C, 70.15; H, 7.06; N, 20.45. Found: C,69.90; H, 6.95; N, 20.13.

Example 13141-[3-(3-Isopropylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Isobutyraldehyde (3 mL, 33.0 mmol) and aqueous sodium hydroxide solution(50% w/w, 1.5 mL) were added sequentially to a solution of hydroxylaminehydrochloride (2.52 g, 36.3 mmol) in ethanol (40 mL) and water (80 mL)and stirred at ambient temperature for 17 hours. The pH of the solutionwas adjusted to 12 with 5 mL of 1 N sodium hydroxide solution andextracted with dichloromethane. The combined organic portions werewashed sequentially with water and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure and high vacuum toobtain 1.863 g of 2-methyl-propionaldehyde oxime.

Part B

N-Chlorosuccinimide (2.85 g, 21.4 mmol) was added in one portion to2-methyl-propionaldehyde oxime (1.863 g, 21.4 mmol) in DMF contained ina reaction vessel cooled with an ice bath. After 10 minutes, the icebath was removed, and the mixture was allowed to warm to ambienttemperature. The solution was added to a solution of the alkyne preparedin Parts A through F of Example 614 (3.74 g, 7.53 mmol) in DMF (40 mL)cooled by an ice bath. After 1 minute, triethylamine was added to thesolution which precipitated. After a couple of minutes, the reaction washeated to 50° C. for 4.7 hours, followed by stirring at ambienttemperature for 3 days. The reaction was diluted with dichloromethane,washed with 1 N potassium hydroxide, dried over sodium sulfate,filtered, and purified via column chromatography on silica gel (450 geluting with 30-40% ethyl acetate in hexane) to afford 1.84 g ofmaterial as an amber oil.

Part C

6 M Hydrochloric acid solution in ethanol (10 mL) was added to thematerial obtained from Part B (1.84 g, 3.16 mmol) and stirred at 60° C.for 2.5 hours. The reaction mixture pH was adjusted to 14 with dropwiseaddition of 1 N potassium hydroxide solution and concentrated underreduced pressure. The residue was extracted with dichloromethane and thecombined organic layers were washed sequentially with water and brine,dried over magnesium sulfate, filtered, and concentrated to afford awhite solid. The material was triturated with ether, filtered, and driedto yield 0.9737 g of1-[3-(3-isopropylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amineas a white powder, mp 147.0-149° C.

Anal. calcd for C₂₂H₃₁N₅O.0.05 CH₂Cl₂: C, 68.65; H, 8.13; N, 18.15.Found: C, 68.47; H, 8.31;N, 18.19.

Example 1315N-[2-(4-Amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-isopropylurea

Triethylamine (2.84 mL, 20.4 mmol) was added to a suspension of1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 50) (1.0 g, 4.08 mmol) indichloromethane (50 mL) and cooled to 4° C. Isopropyl isocyanate (0.44mL, 4.48 mmol) was added dropwise to the reaction mixture and maintainedat ambient temperature for 16 hours. The reaction mixture was dilutedwith chloroform (50 mL) and the precipitate was collected by filtration,washed with water, and dried under reduced pressure to affordN-[2-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-isopropylureaas tan needles, mp 237-238° C.

MS (APCI) m/z 331.24 (M+H)⁺;

Anal. calcd for C₁₇H₂₆N₆O.0.06CHCl₃: C, 60.70; H, 7.78; N, 24.89. Found:C, 60.34; H, 8.36; N, 24.64.

Example 1316N-[2-(4-Amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]morpholine4-carboxamide

Triethylamine (2.84 mL, 20.4 mmol) was added to a suspension of1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine(prepared as described in Example 50) (1.0 g, 4.08 mmol) indichloromethane (50 mL) and cooled to 4° C. 4-Morpholinecarbonylchloride (0.61 g, 4.08 mmol) was added in dichloromethane (5 mL)dropwise over 5 minutes to the reaction mixture and maintained atambient temperature for 16 hours. The reaction mixture was diluted withdichloromethane (50 mL) and washed sequentially with water (50 mL), 4%sodium bicarbonate (2×50 mL), water (50 mL), and brine (50 mL). Thecombined organic layers were concentrated under reduced pressure and theresidue was purified via column chromatography on silica gel (80 g,eluting with mixtures of chloroform and CMA). The material wascrystallized from acetonitrile to provideN-[2-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]morpholine-4-carboxamideas orange needles, mp 187-188° C.

MS (APCI) m/z 359.21 (M+H)⁺;

Anal. calcd for C₁₈H₂₆N₆O₂: C, 60.32; H, 7.31; N, 23.45. Found: C,60.10; H, 7.34; N, 23.68.

Example 1317N-(1-Isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)acetamide

Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30mL) and cooled to 4° C. Acetyl chloride (0.255 g, 3.24 mmol) was addedin dichloromethane (5 mL) dropwise over 5 minutes to the reactionmixture and maintained at ambient temperature for 16 hours. The reactionmixture was diluted with dichloromethane (25 mL) and washed sequentiallywith water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), andbrine (25 mL). The combined organic layers were concentrated underreduced pressure and the residue was purified via column chromatographyon silica gel (80 g, eluting with 0-20% CMA/chloroform), concentratedunder reduced pressure, and recrystallized from diethyl ether to yield0.49 g ofN-(1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)acetamide aswhite crystals, mp 130-131° C.

MS (APCI) m/z 297.16 (M+H)⁺;

Anal. calcd for C₁₇H₂₀N₄O:C, 68.90; H, 6.80; N, 18.90. Found: C, 68.96;H, 6.64; N, 19.14.

Example 1318 Ethyl1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamate

Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (preparedas described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30mL) and cooled to 4° C. Ethyl chloroformate (0.352 g, 3.24 mmol) wasadded in dichloromethane (5 mL) dropwise over 5 minutes to the reactionmixture and maintained at ambient temperature for 16 hours. The reactionmixture was diluted with dichloromethane (25 mL) and washed sequentiallywith water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), andbrine (25 mL). The combined organic layers were concentrated underreduced pressure and the residue was purified via column chromatographyon silica gel (80 g, eluting with 0-10% CMA/chloroform), concentratedunder reduced pressure, and recrystallized from diethyl ether to afford0.45 g of ethyl1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamate as whitecrystals, mp 120-121° C.

MS (APCI) m/z 327.18 (M+H)⁺;

Anal. calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.16. Found: C,66.32; H, 6.62; N, 17.48.

Example 1319 Ethyl2-methyl-1-{2-[(methylsulfonyl)amino]ethyl}-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamate

Triethylamine (0.044 g, 0.4 mmol) was added to a suspension of the amineof Example 128 (0.07 g, 0.2 mmol) in dichloromethane (5 mL) and cooledto 4° C. Ethyl chloroformate (0.024 g, 0.2 mmol) was added indichloromethane (1 mL) dropwise over 5 minutes to the reaction mixtureand maintained at ambient temperature for 2 hours. The reaction mixturewas diluted with dichloromethane (5 mL) and washed sequentially withwater (5 mL), 4% sodium bicarbonate (2×5 mL), water (5 mL), and brine (5mL). The combined organic layers were concentrated under reducedpressure and the residue was purified via column chromatography onsilica gel (80 g, eluting with 5-30% CMA/chloroform), concentrated underreduced pressure, and recrystallized from acetonitrile to yield 0.044 gof ethyl2-methyl-1-{²-[(methylsulfonyl)amino]ethyl}-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamateas a white solid, mp 214-215° C.

¹H-NMR (300 MHz, DMSO) δ 9.41 (br s, 1H), 7.29 (br s, 1H), 4.11-4.05 (m,5H), 3.27-3.21 (m, 4H), 2.99 (br s, 2H), 2.87(s, 3H), 2.72 (br s, 2H),1.81(br s, 4H), 1.21 (t, J=7.1 Hz, 3H).

MS (APCI) m/z 396.16 (M+H)⁺.

Example 1320 7-(Benzyloxy)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine

Part A

Pyridine (1.30 mL, 16.12 mmol) was added to a suspension of6-benzyloxyindole (3.0 g, 13.44 mmol) in diethylether (20 mL) cooled to4° C. Chloroethyl oxalate (2.02 g, 14.78 mmol) was added in diethylether(7 mL) dropwise over 5 minutes to the reaction mixture and maintained atambient temperature for 20 hours. The reaction mixture was diluted withdiethylether (30 mL) and the yellow precipitate was collected viafiltration and washed with diethylether. The solid was suspended inwater (20 mL), stirred for 10 minutes, and the solid was harvested byfiltration and dried to provide 3.5 g of6-benzyloxy-1H-indol-3-yl)-oxo-acetic acid ethyl ester as a yellowsolid.

Part B

Acetyl chloride (1.49 mL, 21.02 mmol), acetic acid (6M, 1.75 mL), andethylhydrazine oxalate (3.2 g, 21.02 mmol) were sequentially added to asuspension of 6-benzyloxy-1H-indol-3-yl)-oxo-acetic acid ethyl ester(3.4 g, 10.51 mmol) in ethanol (53 mL) and heated at reflux temperatureovernight. The reaction mixture was cooled to ambient temperature andthe insoluble material was removed via filtration. The filtrate wasconcentrated under reduced pressure, purified via column chromatographyon silica gel (80 g, eluting with 0-10% CMA/chloroform), concentratedunder reduced pressure, and recrystallized from acetonitrile to yield1.34 g of 7-benzyloxy-2-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-oneas a brown solid, mp 240-241° C.

Part C

Phosphorous oxychloride (15 mL) was added to7-benzyloxy-2-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (1.20 g,3.76 mmol) and heated at 100° C. for 1 hour. The reaction mixture wascooled to ambient temperature and the poured onto crushed ice whilestirring. 6 N Sodium hydroxide solution was added to the suspension at4° C. and the solid was harvested by filtration and dried to afford 1.23g of 7-benzyloxy-4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline as ayellow solid, mp 155-157° C.

Part D

A mixture of 7-benzyloxy4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline(1.20 g, 3.55 mmol) and 7 N ammonia in methanol (25 mL) was heated in apressure vessel at 150° C. for 24 hours. The reaction mixture wasconcentrated under reduced pressure, purified via column chromatographyon silica gel (eluting with 0-35% CMA/chloroform), concentrated underreduced pressure, and crystallized from acetonitrile to yield 0.93 g of7-(benzyloxy)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a tan solid,mp 229-230° C.

MS (APCI) m/z 319.13 (M+H)⁺;

Anal. calcd for C₁₉H₁₈N₄O.0.1HCl: C, 70.87; H, 5.67; N, 17.40. Found: C,70.66; H, 5.92; N, 17.57.

Example 1321 4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-7-ol

A suspension of 7-benzyloxy-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-ylamine(prepared as described in Example 1320) (0.80 g, 2.51 mmol) in ethanol(80 mL) and methanol (20 mL) and palladium on carbon (10% palladium w/won carbon) (0.4 g, ) were combined in a pressure vessel and placed underhydrogen pressure ((50 psi (3.4×10⁵ Pa)) for 24 hours. The reactionmixture was diluted with DMF (50 mL), filtered through CELITE filteragent, and the filtrate was concentrated under reduced pressure. Theresidue was purified via column chromatography on silica gel (elutingwith 20-50% CMA/chloroform), concentrated under reduced pressure, andcrystallized from acetonitrile to yield 0.31 g of4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-7-ol as a light-yellow solid,mp 214-215° C.

MS (APCI) m/z 229.10 (M+H)⁺;

Anal. calcd for C₁₂H₁₂N₄O:C, 63.15; H, 5.30; N, 24.55. Found: C, 62.91;H, 4.99; N, 24.65.

Exemplary Compounds

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula (IIIa, IIIb, IVa, VIa, VIIa,VIIIa, or IXa) and the following R₁, and R₂ substituents, wherein eachline of the table represents a specific compound.

R₁ R₂ methyl hydrogen methyl methyl methyl ethyl methyl n-propyl methyln-butyl methyl benzyl methyl 2-methoxyethyl methyl 2-hydroxyethyl ethylhydrogen ethyl methyl ethyl ethyl ethyl n-propyl ethyl n-butyl ethylbenzyl ethyl 2-methoxyethyl ethyl 2-hydroxyethyl 2-methylpropyl hydrogen2-methylpropyl methyl 2-methylpropyl ethyl 2-methylpropyl n-propyl2-methylpropyl n-butyl 2-methylpropyl benzyl 2-methylpropyl2-methoxyethyl 2-methylpropyl 2-hydroxyethyl 2-methanesulfonylethylhydrogen 2-methanesulfonylethyl methyl 2-methanesulfonylethyl ethyl2-methanesulfonylethyl n-propyl 2-methanesulfonylethyl n-butyl2-methanesulfonylethyl benzyl 2-methanesulfonylethyl 2-methoxyethyl2-methanesulfonylethyl 2-hydroxyethyl 4-methanesulfonylaminobutylhydrogen 4-methanesulfonylaminobutyl methyl 4-methanesulfonylaminobutylethyl 4-methanesulfonylaminobutyl n-propyl 4-methanesulfonylaminobutyln-butyl 4-methanesulfonylaminobutyl benzyl 4-methanesulfonylaminobutyl2-methoxyethyl 4-methanesulfonylaminobutyl 2-hydroxyethyl2-(2-propanesulfonylamino)ethyl hydrogen 2-(2-propanesulfonylamino)ethylmethyl 2-(2-propanesulfonylamino)ethyl ethyl2-(2-propanesulfonylamino)ethyl n-propyl 2-(2-propanesulfonylamino)ethyln-butyl 2-(2-propanesulfonylamino)ethyl benzyl2-(2-propanesulfonylamino)ethyl 2-methoxyethyl2-(2-propanesulfonylamino)ethyl 2-hydroxyethyl2-(benzenesulfonylamino)ethyl hydrogen 2-(benzenesulfonylamino)ethylmethyl 2-(benzenesulfonylamino)ethyl ethyl 2-(benzenesulfonylamino)ethyln-propyl 2-(benzenesulfonylamino)ethyl n-butyl2-(benzenesulfonylamino)ethyl benzyl 2-(benzenesulfonylamino)ethyl2-methoxyethyl 2-(benzenesulfonylamino)ethyl 2-hydroxyethyl2-(dimethylaminosulfonylamino)ethyl hydrogen2-(dimethylaminosulfonylamino)ethyl methyl2-(dimethylaminosulfonylamino)ethyl ethyl2-(dimethylaminosulfonylamino)ethyl n-propyl2-(dimethylaminosulfonylamino)ethyl n-butyl2-(dimethylaminosulfonylamino)ethyl benzyl2-(dimethylaminosulfonylamino)ethyl 2-methoxyethyl2-(dimethylaminosulfonylamino)ethyl 2-hydroxyethyl 4-hydroxybutylhydrogen 4-hydroxybutyl methyl 4-hydroxybutyl ethyl 4-hydroxybutyln-propyl 4-hydroxybutyl n-butyl 4-hydroxybutyl benzyl 4-hydroxybutyl2-methoxyethyl 4-hydroxybutyl 2-hydroxyethyl 2-aminoethyl hydrogen2-aminoethyl methyl 2-aminoethyl ethyl 2-aminoethyl n-propyl2-aminoethyl n-butyl 2-aminoethyl benzyl 2-aminoethyl 2-methoxyethyl2-aminoethyl 2-hydroxyethyl 2-(cyclopropanecarbonylamino)ethyl hydrogen2-(cyclopropanecarbonylamino)ethyl methyl2-(cyclopropanecarbonylamino)ethyl ethyl2-(cyclopropanecarbonylamino)ethyl n-propyl2-(cyclopropanecarbonylamino)ethyl n-butyl2-(cyclopropanecarbonylamino)ethyl benzyl2-(cyclopropanecarbonylamino)ethyl 2-methoxyethyl2-(cyclopropanecarbonylamino)ethyl 2-hydroxyethyl 2-(benzoylamino)ethylhydrogen 2-(benzoylamino)ethyl methyl 2-(benzoylamino)ethyl ethyl2-(benzoylamino)ethyl n-propyl 2-(benzoylamino)ethyl n-butyl2-(benzoylamino)ethyl benzyl 2-(benzoylamino)ethyl 2-methoxyethyl2-(benzoylamino)ethyl 2-hydroxyethyl 2-(benzoylamino)-2-methylpropylhydrogen 2-(benzoylamino)-2-methylpropyl methyl2-(benzoylamino)-2-methylpropyl ethyl 2-(benzoylamino)-2-methylpropyln-propyl 2-(benzoylamino)-2-methylpropyl n-butyl2-(benzoylamino)-2-methylpropyl benzyl 2-(benzoylamino)-2-methylpropyl2-methoxyethyl 2-(benzoylamino)-2-methylpropyl 2-hydroxyethyl2-(pyridine-3-carbonylamino)ethyl hydrogen2-(pyridine-3-carbonylamino)ethyl methyl2-(pyridine-3-carbonylamino)ethyl ethyl2-(pyridine-3-carbonylamino)ethyl n-propyl2-(pyridine-3-carbonylamino)ethyl n-butyl2-(pyridine-3-carbonylamino)ethyl benzyl2-(pyridine-3-carbonylamino)ethyl 2-methoxyethyl2-(pyridine-3-carbonylamino)ethyl 2-hydroxyethyl2-(2-propanecarbonylamino)ethyl hydrogen 2-(2-propanecarbonylamino)ethylmethyl 2-(2-propanecarbonylamino)ethyl ethyl2-(2-propanecarbonylamino)ethyl n-propyl 2-(2-propanecarbonylamino)ethyln-butyl 2-(2-propanecarbonylamino)ethyl benzyl2-(2-propanecarbonylamino)ethyl 2-methoxyethyl2-(2-propanecarbonylamino)ethyl 2-hydroxyethyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl hydrogen4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl methyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl ethyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl n-propyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl n-butyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl benzyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl 2-methoxyethyl4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl 2-hydroxyethyl2-(3-phenylureido)ethyl hydrogen 2-(3-phenylureido)ethyl methyl2-(3-phenylureido)ethyl ethyl 2-(3-phenylureido)ethyl n-propyl2-(3-phenylureido)ethyl n-butyl 2-(3-phenylureido)ethyl benzyl2-(3-phenylureido)ethyl 2-methoxyethyl 2-(3-phenylureido)ethyl2-hydroxyethyl 2-(3-pyridinylureido)ethyl hydrogen2-(3-pyridinylureido)ethyl methyl 2-(3-pyridinylureido)ethyl ethyl2-(3-pyridinylureido)ethyl n-propyl 2-(3-pyridinylureido)ethyl n-butyl2-(3-pyridinylureido)ethyl benzyl 2-(3-pyridinylureido)ethyl2-methoxyethyl 2-(3-pyridinylureido)ethyl 2-hydroxyethyl2-[3,3-(dimethyl)ureido]ethyl hydrogen 2-[3,3-(dimethyl)ureido]ethylmethyl 2-[3,3-(dimethyl)ureido]ethyl ethyl 2-[3,3-(dimethyl)ureido]ethyln-propyl 2-[3,3-(dimethyl)ureido]ethyl n-butyl2-[3,3-(dimethyl)ureido]ethyl benzyl 2-[3,3-(dimethyl)ureido]ethyl2-methoxyethyl 2-[3,3-(dimethyl)ureido]ethyl 2-hydroxyethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula (IIIa, IIIb, IVa, VIa, VIIa,VIIIa, or IXa) and the following R₁, and R₂ substituents, wherein eachline of the table represents a specific compound.

R₁ R₂ 2-(propylsulfonyl)ethyl hydrogen 2-(propylsulfonyl)ethyl methyl2-(propylsulfonyl)ethyl ethyl 2-(propylsulfonyl)ethyl n-propyl2-(propylsulfonyl)ethyl n-butyl 2-(propylsulfonyl)ethyl benzyl2-(propylsulfonyl)ethyl 2-methoxyethyl 2-(propylsulfonyl)ethyl2-hydroxyethyl 2-hydroxy-2-methylpropyl hydrogen2-hydroxy-2-methylpropyl methyl 2-hydroxy-2-methylpropyl ethyl2-hydroxy-2-methylpropyl n-propyl 2-hydroxy-2-methylpropyl n-butyl2-hydroxy-2-methylpropyl benzyl 2-hydroxy-2-methylpropyl 2-methoxyethyl2-hydroxy-2-methylpropyl 2-hydroxyethyl 2,2-dimethylpropyl hydrogen2,2-dimethylpropyl methyl 2,2-dimethylpropyl ethyl 2,2-dimethylpropyln-propyl 2,2-dimethylpropyl n-butyl 2,2-dimethylpropyl benzyl2,2-dimethylpropyl 2-methoxyethyl 2,2-dimethylpropyl 2-hydroxyethyl2-phenylethyl hydrogen 2-phenylethyl methyl 2-phenylethyl ethyl2-phenylethyl n-propyl 2-phenylethyl n-butyl 2-phenylethyl benzyl2-phenylethyl 2-methoxyethyl 2-phenylethyl 2-hydroxyethyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl hydrogen2-[(cyclohexylcarbonyl)amino]-2-methylpropyl methyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl ethyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl n-propyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl n-butyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl benzyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl 2-methoxyethyl2-[(cyclohexylcarbonyl)amino]-2-methylpropyl 2-hydroxyethyl2-methyl-2-[(methylsulfonyl)amino]propyl hydrogen2-methyl-2-[(methylsulfonyl)amino]propyl methyl2-methyl-2-[(methylsulfonyl)amino]propyl ethyl2-methyl-2-[(methylsulfonyl)ammo]propyl n-propyl2-methyl-2-[(methylsulfonyl)amino]propyl n-butyl2-methyl-2-[(methylsulfonyl)amino]propyl benzyl2-methyl-2-[(methylsulfonyl)amino]propyl 2-methoxyethyl2-methyl-2-[(methylsulfonyl)amino]propyl 2-hydroxyethyl2-(isobutyrylamino)-2-methylpropyl hydrogen2-(isobutyrylamino)-2-methylpropyl methyl2-(isobutyrylamino)-2-methylpropyl ethyl2-(isobutyrylamino)-2-methylpropyl n-propyl2-(isobutyrylamino)-2-methylpropyl n-butyl2-(isobutyrylamino)-2-methylpropyl benzyl2-(isobutyrylamino)-2-methylpropyl 2-methoxyethyl2-(isobutyrylamino)-2-methylpropyl 2-hydroxyethyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl hydrogen2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl methyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl ethyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl n-propyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl n-butyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl benzyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl 2-methoxyethyl2-methyl-2-[(pyridin-3-ylcarbonyl)amino]propyl 2-hydroxyethyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl hydrogen2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl methyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl ethyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl n-propyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl n-butyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl benzyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl 2-methoxyethyl2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl 2-hydroxyethyl2-(acetylamino)-2-methylpropyl hydrogen 2-(acetylamino)-2-methylpropylmethyl 2-(acetylamino)-2-methylpropyl ethyl2-(acetylamino)-2-methylpropyl n-propyl 2-(acetylamino)-2-methylpropyln-butyl 2-(acetylamino)-2-methylpropyl benzyl2-(acetylamino)-2-methylpropyl 2-methoxyethyl2-(acetylamino)-2-methylpropyl 2-hydroxyethyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl hydrogen4-(4-pyridin-2-ylpiperazin-1-yl)butyl methyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl ethyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl n-propyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl n-butyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl benzyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl 2-methoxyethyl4-(4-pyridin-2-ylpiperazin-1-yl)butyl 2-hydroxyethyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl hydrogen3-(3-pyridin-3-ylisoxazol-5-yl)propyl methyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl ethyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl n-propyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl n-butyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl benzyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl 2-methoxyethyl3-(3-pyridin-3-ylisoxazol-5-yl)propyl 2-hydroxyethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula (IIIa, IIIb, IVa, VIa, VIIa,VIIIa, or IXa) and the following R₁, and R₂ substituents, wherein eachline of the table represents a specific compound.

R₁ R₂ n-butyl hydrogen n-butyl methyl n-butyl ethyl n-butyl n-propyln-butyl n-butyl n-butyl benzyl n-butyl 2-methoxyethyl n-butyl2-hydroxyethyl 4-aminobutyl hydrogen 4-aminobutyl methyl 4-aminobutylethyl 4-aminobutyl n-propyl 4-aminobutyl n-butyl 4-aminobutyl benzyl4-aminobutyl 2-methoxyethyl 4-aminobutyl 2-hydroxyethyl2-amino-2-methylpropyl hydrogen 2-amino-2-methylpropyl methyl2-amino-2-methylpropyl ethyl 2-amino-2-methylpropyl n-propyl2-amino-2-methylpropyl n-butyl 2-amino-2-methylpropyl benzyl2-amino-2-methylpropyl 2-methoxyethyl 2-amino-2-methylpropyl2-hydroxyethyl 4-acetoxybutyl hydrogen 4-acetoxybutyl methyl4-acetoxybutyl ethyl 4-acetoxybutyl n-propyl 4-acetoxybutyl n-butyl4-acetoxybutyl benzyl 4-acetoxybutyl 2-methoxyethyl 4-acetoxybutyl2-hydroxyethyl 4-(methylsulfonyl)butyl hydrogen 4-(methylsulfonyl)butylmethyl 4-(methylsulfonyl)butyl ethyl 4-(methylsulfonyl)butyl n-propyl4-(methylsulfonyl)butyl n-butyl 4-(methylsulfonyl)butyl benzyl4-(methylsulfonyl)butyl 2-methoxyethyl 4-(methylsulfonyl)butyl2-hydroxyethyl 3-(phenylsulfonyl)propyl hydrogen3-(phenylsulfonyl)propyl methyl 3-(phenylsulfonyl)propyl ethyl3-(phenylsulfonyl)propyl n-propyl 3-(phenylsulfonyl)propyl n-butyl3-(phenylsulfonyl)propyl benzyl 3-(phenylsulfonyl)propyl 2-methoxyethyl3-(phenylsulfonyl)propyl 2-hydroxyethyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl hydrogen2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl methyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl ethyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl n-propyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl n-butyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl benzyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl 2-methoxyethyl2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl 2-hydroxyethyl4-(aminosulfonyl)butyl hydrogen 4-(aminosulfonyl)butyl methyl4-(aminosulfonyl)butyl ethyl 4-(aminosulfonyl)butyl n-propyl4-(aminosulfonyl)butyl n-butyl 4-(aminosulfonyl)butyl benzyl4-(aminosulfonyl)butyl 2-methoxyethyl 4-(aminosulfonyl)butyl2-hydroxyethyl 4-[(methylamino)sulfonyl]butyl hydrogen4-[(methylamino)sulfonyl]butyl methyl 4-[(methylamino)sulfonyl]butylethyl 4-[(methylamino)sulfonyl]butyl n-propyl4-[(methylamino)sulfonyl]butyl n-butyl 4-[(methylamino)sulfonyl]butylbenzyl 4-[(methylamino)sulfonyl]butyl 2-methoxyethyl4-[(methylamino)sulfonyl]butyl 2-hydroxyethyl4-[(dimethylamino)sulfonyl]butyl hydrogen4-[(dimethylamino)sulfonyl]butyl methyl 4-[(dimethylamino)sulfonyl]butylethyl 4-[(dimethylamino)sulfonyl]butyl n-propyl4-[(dimethylamino)sulfonyl]butyl n-butyl4-[(dimethylamino)sulfonyl]butyl benzyl 4-[(dimethylamino)sulfonyl]butyl2-methoxyethyl 4-[(dimethylamino)sulfonyl]butyl 2-hydroxyethyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl hydrogen2-[(cyclopropylcarbonyl)amino]-2-methylpropyl methyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl ethyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl n-propyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl n-butyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl benzyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl 2-methoxyethyl2-[(cyclopropylcarbonyl)amino]-2-methylpropyl 2-hydroxyethyl2-methyl-2-(propionylamino)propyl hydrogen2-methyl-2-(propionylamino)propyl methyl2-methyl-2-(propionylamino)propyl ethyl2-methyl-2-(propionylamino)propyl n-propyl2-methyl-2-(propionylamino)propyl n-butyl2-methyl-2-(propionylamino)propyl benzyl2-methyl-2-(propionylamino)propyl 2-methoxyethyl2-methyl-2-(propionylamino)propyl 2-hydroxyethyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl hydrogen2-[(4-fluorobenzoyl)amino]-2-methylpropyl methyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl ethyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl n-propyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl n-butyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl benzyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl 2-methoxyethyl2-[(4-fluorobenzoyl)amino]-2-methylpropyl 2-hydroxyethyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl hydrogen2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl methyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl ethyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl n-propyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl n-butyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl benzyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl 2-methoxyethyl2-[(3,4-difluorobenzoyl)amino]-2-methylpropyl 2-hydroxyethyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl hydrogen2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl methyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl ethyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl n-propyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl n-butyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl benzyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl 2-methoxyethyl2-methyl-2-[(pyridin-4-ylcarbonyl)amino]propyl 2-hydroxyethyl3-(3-methylisoxazol-5-yl)propyl hydrogen 3-(3-methylisoxazol-5-yl)propylmethyl 3-(3-methylisoxazol-5-yl)propyl ethyl3-(3-methylisoxazol-5-yl)propyl n-propyl 3-(3-methylisoxazol-5-yl)propyln-butyl 3-(3-methylisoxazol-5-yl)propyl benzyl3-(3-methylisoxazol-5-yl)propyl 2-methoxyethyl3-(3-methylisoxazol-5-yl)propyl 2-hydroxyethyl3-(3-isopropyllisoxazol-5-yl)propyl hydrogen3-(3-isopropyllisoxazol-5-yl)propyl methyl3-(3-isopropyllisoxazol-5-yl)propyl ethyl3-(3-isopropyllisoxazol-5-yl)propyl n-propyl3-(3-isopropyllisoxazol-5-yl)propyl n-butyl3-(3-isopropyllisoxazol-5-yl)propyl benzyl3-(3-isopropyllisoxazol-5-yl)propyl 2-methoxyethyl3-(3-isopropyllisoxazol-5-yl)propyl 2-hydroxyethyl3-(3-phenylisoxazol-5-yl)propyl hydrogen 3-(3-phenylisoxazol-5-yl)propylmethyl 3-(3-phenylisoxazol-5-yl)propyl ethyl3-(3-phenylisoxazol-5-yl)propyl n-propyl 3-(3-phenylisoxazol-5-yl)propyln-butyl 3-(3-phenylisoxazol-5-yl)propyl benzyl3-(3-phenylisoxazol-5-yl)propyl 2-methoxyethyl3-(3-phenylisoxazol-5-yl)propyl 2-hydroxyethyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl hydrogen4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl methyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl ethyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl n-propyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl n-butyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl benzyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl 2-methoxyethyl4-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)butyl 2-hydroxyethyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl hydrogen4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl methyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl ethyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl n-propyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl n-butyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl benzyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl 2-methoxyethyl4-(3-methyl-1-oxa-2,4-diazaspiro[4.4]non-2-en-4-yl)butyl 2-hydroxyethylpent-4-ynyl hydrogen pent-4-ynyl methyl pent-4-ynyl ethyl pent-4-ynyln-propyl pent-4-ynyl n-butyl pent-4-ynyl benzyl pent-4-ynyl2-methoxyethyl pent-4-ynyl 2-hydroxyethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula (IIIa, IIIb, IVa, VIa, VIIa,VIIIa, or IXa) and the following R₁, and R₂ substituents, wherein eachline of the table represents a specific compound.

IIIa

IIIb

IVa

VIa

VIIa

VIIIa

IXa R₁ R₂ aminomethyl hydrogen aminomethyl methyl aminomethyl ethylaminomethyl n-propyl aminomethyl n-butyl aminomethyl benzyl aminomethyl2-methoxyethyl aminomethyl 2-hydroxyethyl piperidin-4-ylmethyl hydrogenpiperidin-4-ylmethyl methyl piperidin-4-ylmethyl ethylpiperidin-4-ylmethyl n-propyl piperidin-4-ylmethyl n-butylpiperidin-4-ylmethyl benzyl piperidin-4-ylmethyl 2-methoxyethylpiperidin-4-ylmethyl 2-hydroxyethyl (1-benzylpiperidin-4-yl)methylhydrogen (1-benzylpiperidin-4-yl)methyl methyl(1-benzylpiperidin-4-yl)methyl ethyl (1-benzylpiperidin-4-yl)methyln-propyl (1-benzylpiperidin-4-yl)methyl n-butyl(1-benzylpiperidin-4-yl)methyl benzyl (1-benzylpiperidin-4-yl)methyl2-methoxyethyl (1-benzylpiperidin-4-yl)methyl 2-hydroxyethyl(1-acetylpiperidin-4-yl)methyl hydrogen (1-acetylpiperidin-4-yl)methylmethyl (1-acetylpiperidin-4-yl)methyl ethyl(1-acetylpiperidin-4-yl)methyl n-propyl (1-acetylpiperidin-4-yl)methyln-butyl (1-acetylpiperidin-4-yl)methyl benzyl(1-acetylpiperidin-4-yl)methyl 2-methoxyethyl(1-acetylpiperidin-4-yl)methyl 2-hydroxyethyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl hydrogen{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl methyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl ethyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl n-propyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl n-butyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl benzyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl 2-methoxyethyl{1-[(propylamino)carbonyl]piperidin-4-yl)}methyl 2-hydroxyethyl[1-(methylsulfonyl)piperidin-4-yl]methyl hydrogen[1-(methylsulfonyl)piperidin-4-yl]methyl methyl[1-(methylsulfonyl)piperidin-4-yl]methyl ethyl[1-(methylsulfonyl)piperidin-4-yl]methyl n-propyl[1-(methylsulfonyl)piperidin-4-yl]methyl n-butyl[1-(methylsulfonyl)piperidin-4-yl]methyl benzyl[1-(methylsulfonyl)piperidin-4-yl]methyl 2-methoxyethyl[1-(methylsulfonyl)piperidin-4-yl]methyl 2-hydroxyethyl2-[(4-fluorobenzoyl)amino]ethyl hydrogen 2-[(4-fluorobenzoyl)amino]ethylmethyl 2-[(4-fluorobenzoyl)amino]ethyl ethyl2-[(4-fluorobenzoyl)amino]ethyl n-propyl 2-[(4-fluorobenzoyl)amino]ethyln-butyl 2-[(4-fluorobenzoyl)amino]ethyl benzyl2-[(4-fluorobenzoyl)amino]ethyl 2-methoxyethyl2-[(4-fluorobenzoyl)amino]ethyl 2-hydroxyethyl2-[(cyclopropylcarbonyl)amino]ethyl hydrogen2-[(cyclopropylcarbonyl)amino]ethyl methyl2-[(cyclopropylcarbonyl)amino]ethyl ethyl2-[(cyclopropylcarbonyl)amino]ethyl n-propyl2-[(cyclopropylcarbonyl)amino]ethyl n-butyl2-[(cyclopropylcarbonyl)amino]ethyl benzyl2-[(cyclopropylcarbonyl)amino]ethyl 2-methoxyethyl2-[(cyclopropylcarbonyl)amino]ethyl 2-hydroxyethyl 2-(acetylamino)ethylhydrogen 2-(acetylamino)ethyl methyl 2-(acetylamino)ethyl ethyl2-(acetylamino)ethyl n-propyl 2-(acetylamino)ethyl n-butyl2-(acetylamino)ethyl benzyl 2-(acetylamino)ethyl 2-methoxyethyl2-(acetylamino)ethyl 2-hydroxyethyl 2-(propionylamino)ethyl hydrogen2-(propionylamino)ethyl methyl 2-(propionylamino)ethyl ethyl2-(propionylamino)ethyl n-propyl 2-(propionylamino)ethyl n-butyl2-(propionylamino)ethyl benzyl 2-(propionylamino)ethyl 2-methoxyethyl2-(propionylamino)ethyl 2-hydroxyethyl 2-[(methylsulfonyl)amino]ethylhydrogen 2-[(methylsulfonyl)amino]ethyl methyl2-[(methylsulfonyl)amino]ethyl ethyl 2-[(methylsulfonyl)amino]ethyln-propyl 2-[(methylsulfonyl)amino]ethyl n-butyl2-[(methylsulfonyl)amino]ethyl benzyl 2-[(methylsulfonyl)amino]ethyl2-methoxyethyl 2-[(methylsulfonyl)amino]ethyl 2-hydroxyethyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl hydrogen2-(1,1-dioxidoisothiazolidin-2-yl)ethyl methyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl ethyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl n-propyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl n-butyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl benzyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl 2-methoxyethyl2-(1,1-dioxidoisothiazolidin-2-yl)ethyl 2-hydroxyethyl2-{[(ethylamino)carbonyl]amino}ethyl hydrogen2-{[(ethylamino)carbonyl]amino}ethyl methyl2-{[(ethylamino)carbonyl]amino}ethyl ethyl2-{[(ethylamino)carbonyl]amino}ethyl n-propyl2-{[(ethylamino)carbonyl]amino}ethyl n-butyl2-{[(ethylamino)carbonyl]amino}ethyl benzyl2-{[(ethylamino)carbonyl]amino}ethyl 2-methoxyethyl2-{[(ethylamino)carbonyl]amino}ethyl 2-hydroxyethyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl hydrogen2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl methyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl ethyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl n-propyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl n-butyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl benzyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl 2-methoxyethyl2-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl 2-hydroxyethyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl hydrogen2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl methyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl ethyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl n-propyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl n-butyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl benzyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl 2-methoxyethyl2-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl 2-hydroxyethyl2-{[(isopropylamino)carbonyl]amino}ethyl hydrogen2-{[(isopropylamino)carbonyl]amino}ethyl methyl2-{[(isopropylamino)carbonyl]amino}ethyl ethyl2-{[(isopropylamino)carbonyl]amino}ethyl n-propyl2-{[(isopropylamino)carbonyl]amino}ethyl n-butyl2-{[(isopropylamino)carbonyl]amino}ethyl benzyl2-{[(isopropylamino)carbonyl]amino}ethyl 2-methoxyethyl2-{[(isopropylamino)carbonyl]amino}ethyl 2-hydroxyethyl2-[(ethoxycarbonyl)amino]ethyl hydrogen 2-[(ethoxycarbonyl)amino]ethylmethyl 2-[(ethoxycarbonyl)amino]ethyl ethyl2-[(ethoxycarbonyl)amino]ethyl n-propyl 2-[(ethoxycarbonyl)amino]ethyln-butyl 2-[(ethoxycarbonyl)amino]ethyl benzyl2-[(ethoxycarbonyl)amino]ethyl 2-methoxyethyl2-[(ethoxycarbonyl)amino]ethyl 2-hydroxyethyl2-[(morpholin-4-ylcarbonyl)amino]ethyl hydrogen2-[(morpholin-4-ylcarbonyl)amino]ethyl methyl2-[(morpholin-4-ylcarbonyl)amino]ethyl ethyl2-[(morpholin-4-ylcarbonyl)amino]ethyl n-propyl2-[(morpholin-4-ylcarbonyl)amino]ethyl n-butyl2-[(morpholin-4-ylcarbonyl)amino]ethyl benzyl2-[(morpho1in-4-ylcarbonyl)amino]ethyl 2-methoxyethyl2-[(morpholin-4-ylcarbonyl)amino]ethyl 2-hydroxyethyl hydroxymethylhydrogen hydroxymethyl methyl hydroxymethyl ethyl hydroxymethyl n-propylhydroxymethyl n-butyl hydroxymethyl benzyl hydroxymethyl 2-methoxyethylhydroxymethyl 2-hydroxyethyl 2-methyl-2-(methylsulfonyl)propyl hydrogen2-methyl-2-(methylsulfonyl)propyl methyl2-methyl-2-(methylsulfonyl)propyl ethyl2-methyl-2-(methylsulfonyl)propyl n-propyl2-methyl-2-(methylsulfonyl)propyl n-butyl2-methyl-2-(methylsulfonyl)propyl benzyl2-methyl-2-(methylsulfonyl)propyl 2-methoxyethyl2-methyl-2-(methylsulfonyl)propyl 2-hydroxyethyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl hydrogen2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl methyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl ethyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl n-propyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl n-butyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl benzyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl 2-methoxyethyl2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl 2-hydroxyethyl3-[(methylsulfonyl)amino]propyl hydrogen 3-[(methylsulfonyl)amino]propylmethyl 3-[(methylsulfonyl)amino]propyl ethyl3-[(methylsulfonyl)amino]propyl n-propyl 3-[(methylsulfonyl)amino]propyln-butyl 3-[(methylsulfonyl)amino]propyl benzyl3-[(methylsulfonyl)amino]propyl 2-methoxyethyl3-[(methylsulfonyl)amino]propyl 2-hydroxyethyl 2-cyano-2-methylpropylhydrogen 2-cyano-2-methylpropyl methyl 2-cyano-2-methylpropyl ethyl2-cyano-2-methylpropyl n-propyl 2-cyano-2-methylpropyl n-butyl2-cyano-2-methylpropyl benzyl 2-cyano-2-methylpropyl 2-methoxyethyl2-cyano-2-methylpropyl 2-hydroxyethyl 3-(5-butylisoxazol-3-yl)propylhydrogen 3-(5-butylisoxazol-3-yl)propyl methyl3-(5-butylisoxazol-3-yl)propyl ethyl 3-(5-butylisoxazol-3-yl)propyln-propyl 3-(5-butylisoxazol-3-yl)propyl n-butyl3-(5-butylisoxazol-3-yl)propyl benzyl 3-(5-butylisoxazol-3-yl)propyl2-methoxyethyl 3-(5-butylisoxazol-3-yl)propyl 2-hydroxyethyl3-(5-phenylisoxazol-3-yl)propyl hydrogen 3-(5-phenylisoxazol-3-yl)propylmethyl 3-(5-phenylisoxazol-3-yl)propyl ethyl3-(5-phenylisoxazol-3-yl)propyl n-propyl 3-(5-phenylisoxazol-3-yl)propyln-butyl 3-(5-phenylisoxazol-3-yl)propyl benzyl3-(5-phenylisoxazol-3-yl)propyl 2-methoxyethyl3-(5-phenylisoxazol-3-yl)propyl 2-hydroxyethyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl hydrogen3-(5-pyridin-3-ylisoxazol-3-yl)propyl methyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl ethyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl n-propyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl n-butyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl benzyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl 2-methoxyethyl3-(5-pyridin-3-ylisoxazol-3-yl)propyl 2-hydroxyethyl4-(hydroxyimino)butyl hydrogen 4-(hydroxyimino)butyl methyl4-(hydroxyimino)butyl ethyl 4-(hydroxyimino)butyl n-propyl4-(hydroxyimino)butyl n-butyl 4-(hydroxyimino)butyl benzyl4-(hydroxyimino)butyl 2-methoxyethyl 4-(hydroxyimino)butyl2-hydroxyethyl 4-(methoxyimino)butyl hydrogen 4-(methoxyimino)butylmethyl 4-(methoxyimino)butyl ethyl 4-(methoxyimino)butyl n-propyl4-(methoxyimino)butyl n-butyl 4-(methoxyimino)butyl benzyl4-(methoxyimino)butyl 2-methoxyethyl 4-(methoxyimino)butyl2-hydroxyethyl 5-amino-5-(hydroxyimino)pentyl hydrogen5-amino-5-(hydroxyimino)pentyl methyl 5-amino-5-(hydroxyimino)pentylethyl 5-amino-5-(hydroxyimino)pentyl n-propyl5-amino-5-(hydroxyimino)pentyl n-butyl 5-amino-5-(hydroxyimino)pentylbenzyl 5-amino-5-(hydroxyimino)pentyl 2-methoxyethyl5-amino-5-(hydroxyimino)pentyl 2-hydroxyethyl 3-(1H-pyrrol-3-yl)propylhydrogen 3-(1H-pyrrol-3-yl)propyl methyl 3-(1H-pyrrol-3-yl)propyl ethyl3-(1H-pyrrol-3-yl)propyl n-propyl 3-(1H-pyrrol-3-yl)propyl n-butyl3-(1H-pyrrol-3-yl)propyl benzyl 3-(1H-pyrrol-3-yl)propyl 2-methoxyethyl3-(1H-pyrrol-3-yl)propyl 2-hydroxyethyl3-(1-benzyl-1H-pyrrol-3-yl)propyl hydrogen3-(1-benzyl-1H-pyrrol-3-yl)propyl methyl3-(1-benzyl-1H-pyrrol-3-yl)propyl ethyl3-(1-benzyl-1H-pyrrol-3-yl)propyl n-propyl3-(1-benzyl-1H-pyrrol-3-yl)propyl n-butyl3-(1-benzyl-1H-pyrrol-3-yl)propyl benzyl3-(1-benzyl-1H-pyrrol-3-yl)propyl 2-methoxyethyl3-(1-benzyl-1H-pyrrol-3-yl)propyl 2-hydroxyethyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl hydrogen3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl methyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl ethyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl n-propyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl n-butyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl benzyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl 2-methoxyethyl3-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)propyl 2-hydroxyethyl

Compounds of the invention have been found to modulate cytokinebiosynthesis by inducing the production of interferon a and/or tumornecrosis factor a when tested using the method described below.

Cytokine Induction in Human Cells

An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon (α) andtumor necrosis factor (α) (IFN-α and TNF-α, respectively) secreted intoculture media as described by Testerman et. al. in “Cytokine Inductionby the Immunomodulators Imiquimod and S-27609”, Journal of LeukocyteBiology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Amersham Biosciences Piscataway, N.J.). Blood isdiluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank'sBalanced Salts Solution (HBSS). Alternately, whole blood is placed inAccuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, Fla.)centrifuge frit tubes containing density gradient medium. The PBMC layeris collected and washed twice with DPBS or HBSS and re-suspended at4×10⁶cells/mL in RPMI complete. The PBMC suspension is added to 96 wellflat bottom sterile tissue culture plates containing an equal volume ofRPMI complete media containing test compound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM. Controls include cell sampleswith media only, cell samples with DMSO only (no compound), and cellsamples with reference compound.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(usually 30-0.014 μM). The final concentration of PBMC suspension is2×10⁶ cells/mL. The plates are covered with sterile plastic lids, mixedgently and then incubated for 18 to 24 hours at 37° C. in a 5% carbondioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200×g) at 4° C. The cell-free culture supernatant isremoved and transferred to sterile polypropylene tubes. Samples aremaintained at −30 to −70° C. until analysis. The samples are analyzedfor IFN-α by ELISA and for TNF-α by IGEN/Bio Veris Assay.

Interferon (α) and Tumor Necrosis Factor (α) Analysis

IFN-α concentration is determined with a human multi-subtypecolorimetric sandwich ELISA (Catalog Number 41105) from PBL BiomedicalLaboratories, Piscataway, N.J. Results are expressed in pg/mL.

The TNF-α concentration is determined by ORIGEN M-Series Immunoassay andread on an IGEN M-8 analyzer from BioVeris Corporation, formerly knownas IGEN International, Gaithersburg, Md. The immunoassay uses a humanTNF-a capture and detection antibody pair (Catalog Numbers AHC3419 andAHC3712) from Biosource International, Camarillo, Calif. Results areexpressed in pg/mL.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α and IFN-α (y-axis) as a function of compound concentration(x-axis).

Analysis of the data has two steps. First, the greater of the mean DMSO(DMSO control wells) or the experimental background (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α) is subtracted from each reading. Ifany negative values result from background subtraction, the reading isreported as “*”, and is noted as not reliably detectable. In subsequentcalculations and statistics, “*”, is treated as a zero. Second, allbackground subtracted values are multiplied by a single adjustment ratioto decrease experiment to experiment variability. The adjustment ratiois the area of the reference compound in the new experiment divided bythe expected area of the reference compound based on the past 61experiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from the past 61 experiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (μ molar) is thelowest of the tested compound concentrations that induces a responseover a fixed cytokine concentration for the tested cytokine (usually 20pg/mL for IFN-α and 40 pg/mL for TNF-α). The maximal response (pg/mL) isthe maximal response attained in the dose response curve.

Certain compounds of the invention may modulate cytokine biosynthesis byinhibiting production of tumor necrosis factor α (TNF-α) when testedusing the method described below.

TNF-α Inhibition in Mouse Cells

The mouse macrophage cell line Raw 264.7 is used to assess the abilityof compounds to inhibit tumor necrosis factor-α (TNF-α) production uponstimulation by lipopolysaccharide (LPS).

Single Concentration Assay:

Blood Cell Preparation for Culture

Raw cells (ATCC) are harvested by gentle scraping and then counted. Thecell suspension is brought to 3×10⁵ cells/mL in RPMI with 10% fetalbovine serum (FBS). Cell suspension (100 μL) is added to 96-well flatbottom sterile tissues culture plates (Becton Dickinson Labware, LincolnPark, N.J.). The final concentration of cells is 3×10⁴ cells/well. Theplates are incubated for 3 hours. Prior to the addition of test compoundthe medium is replaced with colorless RPMI medium with 3 % FBS.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. Compounds are tested at 5 μM. LPS(Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich) isdiluted with colorless RPMI to the EC₇₀ concentration as measured by adose response assay.

Incubation

A solution of test compound (1 μl) is added to each well. The plates aremixed on a microtiter plate shaker for 1 minute and then placed in anincubator. Twenty minutes later the solution of LPS (1 μL, EC₇₀concentration ˜10 ng/ml) is added and the plates are mixed for 1 minuteon a shaker. The plates are incubated for 18 to 24 hours at 37° C. in a5% carbon dioxide atmosphere.

TNF-α Analysis

Following the incubation the supernatant is removed with a pipet. TNF-αconcentration is determined by ELISA using a mouse TNF-α kit (fromBiosource International, Camarillo, Calif.). Results are expressed inpg/mL. TNF-α expression upon LPS stimulation alone is considered a 100%response.

Dose Response Assay:

Blood Cell Preparation for Culture

Raw cells (ATCC) are harvested by gentle scraping and then counted. Thecell suspension is brought to 4×10⁵ cells/mL in RPMI with 10 % FBS. Cellsuspension (250 μL) is added to 48-well flat bottom sterile tissuesculture plates (Costar, Cambridge, Mass.). The final concentration ofcells is 1×10⁵ cells/well. The plates are incubated for 3 hours. Priorto the addition of test compound the medium is replaced with colorlessRPMI medium with 3 % FBS.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. Compounds are tested at 0.03, 0.1, 0.3, 1, 3, 5and 10 μM. LPS (Lipopolysaccaride from Salmonella typhimurium,Sigma-Aldrich) is diluted with colorless RPMI to the EC₇₀ concentrationas measured by dose response assay.

Incubation

A solution of test compound (200 μl) is added to each well. The platesare mixed on a microtiter plate shaker for 1 minute and then placed inan incubator. Twenty minutes later the solution of LPS (200 μL, EC₇₀concentration ˜10 ng/ml) is added and the plates are mixed for 1 minuteon a shaker. The plates are incubated for 18 to 24 hours at 37° C. in a5% carbon dioxide atmosphere.

TNF-α Analysis

Following the incubation the supernatant is removed with a pipet. TNF-αconcentration is determined by ELISA using a mouse TNF-α kit (fromBiosource International, Camarillo, Calif.). Results are expressed inpg/mL. TNF-α expression upon LPS stimulation alone is considered a 100%response.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. The presentinvention has been described with reference to several embodimentsthereof. The foregoing illustrative embodiments and examples have beenprovided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention is intended to be limitedonly by the claims that follow.

1. A compound of the formula (I):

wherein: R_(A) and R_(B) are each independently selected from the groupconsisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and—N(R₉)₂; or when taken together, R_(A) and R_(B) form a fused aryl ringor heteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R′″ groups; or when takentogether, R_(A) and R_(B) form a fused 5 to 7 membered saturated ring,optionally containing one heteroatom selected from the group consistingof N and S, and unsubstituted or substituted by one or more R groups; Ris selected from the group consisting of: halogen, hydroxy, alkyl,alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R′ and R″ areindependently selected from the group consisting of hydrogen andnon-interfering substitutents; R′″ is a non-interfering substitutent;and R₉ is selected from the group consisting of hydrogen and alkyl; withthe proviso that at least one of R_(A), R_(B), R′, or R″ is other thanhydrogen; and with the further proviso that when R_(A) and R_(B) form abenzene ring unsubstituted or substituted with chloro, and R′ ishydrogen, then R″ is other than phenyl or phenyl substituted withmethyl, methoxy, chloro, or fluoro; or a pharmaceutically acceptablesalt thereof. 2-8. (canceled)
 9. A compound of the formula (II):

wherein: R_(A1) and R_(B1) are each independently selected from thegroup consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy,alkylthio and —N(R₉)₂; or when taken together, R_(A1) and R_(B1) form afused aryl ring or heteroaryl ring containing one heteroatom selectedfrom the group consisting of N and S wherein the aryl or heteroaryl ringis unsubstituted or substituted by one or more R groups, or substitutedby one R₃ group, or substituted by one R₃ group and one R group; or whentaken together, R_(A1) and R_(B1) form a fused 5 to 7 membered saturatedring, optionally containing one heteroatom selected from the groupconsisting of N and S, and unsubstituted or substituted by one or more Rgroups; R is selected from the group consisting of: halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₁ isselected from the group consisting of: —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄,and —X—R₅; R₂ is selected from the group consisting of: —R₄, —X—R₄,—X—Y—R₄, and —X—R₅; R₃ is selected from the group consisting of: -Z-R₄,-Z-X—R₄, -Z-X—Y—R₄, -Z-X—Y—X—Y—R₄, and -Z-X—R₅; X is selected from thegroup consisting of alkylene, alkenylene, alkynylene, arylene,heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, andalkynylene groups can be optionally interrupted or terminated byarylene, heteroarylene or heterocyclylene and optionally interrupted byone or more —O— groups; Y is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—, —C(═N—O—R₈)—NH—, —CH(—N(—O—R₈)-Q-R₄)—,

Z is a bond or —O—; R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; with the provisothat at least one of R_(A1) , R_(B1), R₁, or R₂ is other than hydrogen;and with the further proviso that when R_(A1) and R_(B1) form a fusedbenzene ring unsubstituted or substituted with chloro, and R₁ ishydrogen, then R₂ is other than phenyl or phenyl substituted withmethyl, methoxy, chloro, or fluoro; or a pharmaceutically acceptablesalt thereof. 10-16. (canceled)
 17. A compound of the formula (III):

wherein: R is selected from the group consisting of: halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₁ isselected from the group consisting of: —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄,and —X—R₅; R₂ is selected from the group consisting of: —R₄, —X—R₄,—X—Y—R₄, and —X—R₅; R₃ is selected from the group consisting of: Z-R₄,-Z-X—R₄, -Z-X—Y—R₄, -Z-X—Y—X—Y—R₄, and -Z-X—R₅; n is 0 to 4; m is 0 or1; with the proviso that when m is 1, then n is 0 or 1; X is selectedfrom the group consisting of alkylene, alkenylene, alkynylene, arylene,heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, andalkynylene groups can be optionally interrupted or terminated byarylene, heteroarylene or heterocyclylene and optionally interrupted byone or more —O— groups; Y is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)2—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—, —C(═N—O—R₈)—NH—, —CH(—N(—O—R₈)-Q-R₄)—,

Z is a bond or —O—; R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; with the provisothat when RI is hydrogen, m is 0, and R is chloro, then R₂ is other thanphenyl or phenyl substituted with methyl, methoxy, chloro, or fluoro; ora pharmaceutically acceptable salt thereof. 18-23. (canceled)
 24. Thecompound or salt of claim 17 wherein R₁ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methylpropyl,2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl,2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl. 25-29. (canceled)
 30. A compound selectedfrom the group consisting of the formulas (IV, V, VI, and VII):

wherein: R is selected from the group consisting of: halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₁ isselected from the group consisting of: —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄,and —X—R₅; R₂ is selected from the group consisting of: —R₄, —X—R₄,—X—Y—R₄, and —X—R₅; R₃ is selected from the group consisting of: -Z-R₄,-Z-X—R₄, -Z-X—Y—R₄, -Z-X—Y—X—Y—R₄, and -Z-X—R₅; n is 0 or 1; m is O or1; X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups; Y is selected fromthe group consisting of: —O—, —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—,—C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,—O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—,—C(═N—O—R₈)—NH—, —CH(—N(—O—R₈)-Q-R₄)

Z is a bond or —O—; R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; or apharmaceutically acceptable salt thereof. 31-38. (canceled)
 39. Thecompound or salt of claim 30 wherein R₁ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methylpropyl,2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl,2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl.
 40. A compound of the formula (VIII):

wherein: R is selected from the group consisting of: halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₁ isselected from the group consisting of: —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄,and —X—R₅; R₂ is selected from the group consisting of: —R₄, —X—R₄,—X—Y—R₄, and —X—R₅; n is 0 to 4; X is selected from the group consistingof alkylene, alkenylene, alkynylene, arylene, heteroarylene, andheterocyclylene wherein the alkylene, alkenylene, and alkynylene groupscan be optionally interrupted or terminated by arylene, heteroarylene orheterocyclylene and optionally interrupted by one or more —O— groups; Yis selected from the group consisting of: —O—, —S(O)₀₋₂—, —S(O)₂—N(R₈)—,—C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,—O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—,—C(═N—O—R₈)—NH—, —CH(—N(—O—R₈)-Q-R₄)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; or apharmaceutically acceptable salt thereof. 41-46. (canceled)
 47. Thecompound or salt of claim 40 wherein R, is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methylpropyl,2,2-dimethylpropyl, 2-cyclohexylethyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl, and2-hydroxyethyl.
 48. A compound of the formula (IX):

wherein: R_(A2) and R_(B2) are each independently selected from thegroup consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy,alkylthio, and —N(R₉)₂; R₁ is selected from the group consisting of:—R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄, and —X—R₅; R₂ is selected from thegroup consisting of: —R₄, —X—R₄, —X—Y—R₄, and —X—R₅; X is selected fromthe group consisting of alkylene, alkenylene, alkynylene, arylene,heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, andalkynylene groups can be optionally interrupted or terminated byarylene, heteroarylene or heterocyclylene and optionally interrupted byone or more —O— groups; Y is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R,6)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(N—O—R₈)—, —C(═N—O—R₈)—NH—, —CH(—N(—O—R_(8l )-Q-R) ₄)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; with the provisothat at least one of R_(A2), R_(B2), R₁, or R₂ is other than hydrogen;or a pharmaceutically acceptable salt thereof. 49-54. (canceled)
 55. Thecompound or salt of claim 48 wherein R₁ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methylpropyl,2,2-dimethylpropyl, 2-cyclohexylethyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; R₂ is selected from the group consisting ofmethyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, andbenzyl, and R_(A2) and R_(B2) are each methyl.
 56. A compound of theformula (Ia):

wherein: R_(A3) and R_(B3) are each independently selected from thegroup consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy,alkylthio, and —N(R₉)₂; or when taken together, R_(A3) and R_(B3) form afused aryl ring or heteroaryl ring containing one heteroatom or 5 to 7membered saturated ring optionally containing one heteroatom wherein theheteroatom is selected from the group consisting of N and S and whereinthe aryl, heteroaryl, or 5 to 7 membered saturated ring optionallycontaining one heteroatom is unsubstituted or substituted by one or morenon-interfering substituents; R′ and R″ are independently selected fromthe group consisting of hydrogen and non-interfering substitutents; andR₉ is selected from the group consisting of hydrogen and alkyl; with theproviso that at least one of R_(A3), R_(B3), R′, or R″ is other thanhydrogen; and with the further proviso that when R_(A3) and R_(B3) forma benzene ring unsubstituted or substituted with chloro, and R′ ishydrogen, then R″ is other than phenyl or phenyl substituted withmethyl, methoxy, chloro, or fluoro; or a pharmaceutically acceptablesalt thereof. 57-60. (canceled)
 61. A compound of the following formula(LXXX):

wherein: R is selected from the group consisting of: halogen, alkyl,alkenyl, trifluoromethyl, and dialkylamino; n is 0 or 1; R₁ is selectedfrom the group consisting of: —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄, and—X—R₅; R₂ is selected from the group consisting of: —R₄, —X—R₄, —X—Y—R₄,and —X—R₅; R_(3a) is selected from the group consisting of: —Y′—R₄,

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated by arylene, heteroarylene or heterocyclyleneand optionally interrupted by one or more —O— groups; Y is selected fromthe group consisting of: —O—, —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—,—C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,—O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—,—C(═N—O—R₈)—NH—, —CH(—N(—O—R₈)-Q-R₄)—,

Y′ is selected from the group consisting of —S(O)₂—, —S(O)₂—N(R₈)—,—C(R₆)—, —C(R₆)—O—, and —C(R₆)—N(R₈)—; R₄ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)—N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; or apharmaceutically acceptable salt thereof.
 62. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt of claim 1 in combination with a pharmaceutically acceptablecarrier.
 63. A method of inducing cytokine biosynthesis in an animalcomprising administering an effective amount of a compound or salt ofclaim 1 to the animal.
 64. A method of treating a viral disease in ananimal comprising administering a therapeutically effective amount of acompound or salt of claim 1 to the animal.
 65. A method of treating aneoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of claim 1 to theanimal.
 66. A compound of the formula (II-1):

wherein: Y″ is selected from the group consisting of —C(O)—, —C(O)—O—,and —C(═NR₉)—; R₁₁ is alkyl that is unsubstituted or substituted by oneor more substituents selected from the group consisting of halogen,hydroxy, nitro, cyano, carboxy, C₁₋₄ alkoxy, aryl, heteroaryl, arylC₁₋₄alkylenyl, heteroarylC₁₋₄ alkylenyl, haloC₁₋₄ alkyl, haloC₁₋₄ alkoxy,—O—C(O)—CH₃, —CO₂CH₃, —CONH₂, —O—CH₂—CONH₂, —NH₂, and —SO₂—NH₂; R_(A1)and R_(B1) are each independently selected from the group consisting of:hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio and —N(R₉)₂; orwhen taken together, R_(A1) and R_(B1) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups, or substituted byone R₃ group, or substituted by one R₃ group and one R group; or whentaken together, R_(A1) and R_(B1) form a fused 5 to 7 membered saturatedring, optionally containing one heteroatom selected from the groupconsisting of N and S, and unsubstituted or substituted by one or more Rgroups; R is selected from the group consisting of: halogen, hydroxy,alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R₉)₂; R₁ isselected from the group consisting of: —R₄, —X—R₄, —X—Y—R₄, —X—Y—X—Y—R₄,and —X—R₅; R₂ is selected from the group consisting of: —R₄, —X—R₄,—X—Y—R₄, and —X—R₅; R₃ is selected from the group consisting of: -Z-R₄,-Z-X—R₄, -Z-X—Y—R₄, -Z—X—Y—X—Y—R₄, and -Z-X—R₅; X is selected from thegroup consisting of alkylene, alkenylene, alkynylene, arylene,heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, andalkynylene groups can be optionally interrupted or terminated byarylene, heteroarylene or heterocyclylene and optionally interrupted byone or more —O— groups; Y is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—, —C(═N—O—R₈)—NH—, —CH(—N(—O—R₈)-Q-R₄)—,

Z is a bond or —O—; R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selected fromthe group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, —C(R₆)—S—, and—C(R₆)-N(OR₉)—; V is selected from the group consisting of —C(R₆)—,—O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the groupconsisting of a bond, —C(O)—, and —S(O)₂—; and a and b are independentlyintegers from 1 to 6 with the proviso that a +b is ≦7; with the provisothat at least one of R_(A1) , R_(B1) , RI, or R₂ is other than hydrogen;and with the further proviso that when R_(A1) and R_(B1) form a fusedbenzene ring unsubstituted or substituted with chloro, and R₁ ishydrogen, then R₂ is other than phenyl or phenyl substituted withmethyl, methoxy, chloro, or fluoro; or a pharmaceutically acceptablesalt thereof.
 67. (canceled)
 68. The compound or salt of claim 9 whereinR₁ is selected from the group consisting of methyl, ethyl, propyl,butyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino}ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl.
 69. The compound or salt of claim 61 whereinR₁ is selected from the group consisting of methyl, ethyl, propyl,butyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino }ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl.
 70. The compound or salt of claim 66 whereinR₁ is selected from the group consisting of methyl, ethyl, propyl,butyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl,2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl,2-methyl-2-[(methylsulfonyl)amino]propyl,2-[(cyclohexylcarbonyl)amino]-2-methylpropyl,2-{[(isopropylamino)carbonyl]amino }ethyl,4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl,3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and4-methanesulfonylaminobutyl; and R₂ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl,2-hydroxyethyl, and benzyl.